The series details events in the life of Dr Sloan Parker (Debra Messing), an anthropologist studying genetic variances in human populations, and various associates, friend and enemies. Her mentor, Dr Ann Coulter, is a geneticist commonly called to court to testify on matters of DNA evidence in major cases.

Dr Coulter is secretly working on a theory that certain persons found to be guilty of exceptionally atrocious crimes may have a genetic basis for their criminal nature. She has collected genetic samples from a variety of serial killers and other perpetrators of criminal atrocities. Dr Coulter is a scientific witness in a trial of an accused serial killer, who escapes by methods which are both extremely ingenious and extremely vicious. He manages to track down and murder Dr Coulter. Dr Coulter's body is discovered by her protege, Dr Sloan Parker. Dr Parker also discovers hidden notes, files, data, and an interpretative computer system. By comparing the average human genome with a genome averaged from a collection of genetic samples of heinous criminals -- especially serial killers -- Dr Coulter has discovered a commonalities between the criminals which amount to a difference from humanity. Persons bearing this particular genetic signature are no more (and no less) human than chimpanzees. They share only 98.6 percent of their genetic material with Homo Sapiens.

The first few episodes of the series has a major story arc that deals mostly with Dr Parker coming to grips with the murder of her mentor at the hands of an extremely vicious killer, and coming to realize that her mentor's killer was technically not a Man, but rather a member of a different species. She shares the data and the comparative DNA analysis with fellow scientists, some law-enforcement personnel, and a few others, and all come to realize that Dr Coulter hasn't just identified a few random mutants, but a stable offshoot of the mainstream of humanity. Various theories emerge and are discussed, and contrasts with the mainstream-humanity supplantation and eradication of the Neandertal are explored. The summary concept theory is that in the same way that Homo Sapiens supplanted the cold-adapted Neandertal at the end of the last Ice Age, human-initiated global warming is providing ideal environments for a species adapted to higher temperatures than are easily endured by mainstream humans.

Another major story arc covers the escaped serial killer and his cheerfully murderous rampage across a wide swatch of California. Though he is not close to being apprehended, it's easy to follow the trail of corpses he leaves in his wake. He appears to be heading back towards Dr Parker. Dr Parker, meanwhile, makes the acquaintance of a Federal agent, Tom Daniels (Adam Storke), determined to be the one who captures the serial killer. It becomes apparent that he has reasons other than the usual motives. He eventually reveals himself to be a member of the "new species". He also cautions all involved that they don't know what they're dealing with; this isn't just a bunch of genetically differing mainstream humans with a bent towards criminal attitudes and behavior. He takes them to a location in the desert, and into a cave. In the cave, he shows them a rather large pile of trophies. These are similar to the trophies collected by many serial killers, in this case, a pile of ripped wallets, identity cards, and twisted eyeglass frames. This, he tells them, is what you're dealing with: a different species that collects your possessions like human hunters mount deer heads on the wall of their dens.

Towards the end of the series, the "new species" becomes known as homo dominus or "the Dominants".

The Dominants are known to be smarter and more aggressive, compared to regular humans, and to use any tactic to secure their survival. They are convinced -- in a way which seems almost to be the same sort of ideology as expressed in the Manifest Destiny period of expansion into the North American western regions that would become the USA -- that as the superior form of life, they must dominate their environment and all other forms of competition through any means necessary.

The series portrays interactions between Dominants who express an antipathy that exceeds the merely ideological, and perhaps even the antipathy of racism. They simply cannot stand mainstream humans, consider them defective and lacking, and to be merely entertaining Prey.

The series also portrays an evolving interspecies romance between Dr Parker and Agent Daniels. Not all of the "new species" yield to murderous impulses. Some do in fact -- though with obvious caution, as portrayed in the series -- try to live among mainstream humans with as little friction as possible, and some form varying degrees of alliance with mainstream humans. There is a contrast between instinct, and culture, as portrayed in the series.

This aggression against mainstream humans is portrayed as an instinctual genetic characteristic, for example seen when a young Dominant child attacks three older (as well as larger) human children. On another occasion the introduction of Dominant DNA into a monkey showed the monkey becoming aggressive, attacking and killing the other monkeys within the cage. Furthermore, evolution in mental abilities does seem to be present as a Dominant child demonstrated the ability to cloud the minds of others. It was stated by Tom Daniels, a Dominant posing as an FBI agent, that they have the ability to 'sense the emotions' of others which suggests that they may be partial empaths. However, in order to execute their belief in destroying Homo sapiens, the race has somewhat learnt to suppress their emotions as they do not wish to empathize with the species they are dominating. Finally, a mummified remains of a Dominant girl showed that she possessed four uteruses.

Other significant differences between the "new species" and mainstream humanity included general adaptations to much warmer climates. Though most of the "new species" are portrayed as having appearances very comparable to northern-European stock, they are also portrayed as being very comfortable in deep desert conditions, barely perspiring. They are further portrayed as having a smaller cranium, with greater synaptic interconnectivity. Further, Agent Daniels states that members of the "new species" have an ability to sense each other, in a way which facilitates group operations, drawing a comparison to wolves hunting in a pack.

It was speculated that global warming and other environmental conditions led to a speciation within humanity and that there were 200,000 members of this new branch of Humanity living in a 'shadow society' among humans who were near blissfully unaware of the threat posed by them. Their point of origin, referred to as their version of 'Eden', was a deserted village in Oaxaca, Mexico which was a sacred location for their kind. It was also the location of a mysterious pillar with arcane writings on its surface.

The series has a story-arc exploring the culture of the "new species", insinuating that they might have seeded advanced elements of civilization to the Mesoamerican civilizations. There is some exploration of their knowledge of astronomy, and reference to astronomical cycles, including the arrival of a comet in modern skies, which seems to have been predicted and recorded on the monolith at their earliest-known settlement.

It is interesting to note that there are groups of humans who are aware of the Dominants and collaborate with them in their attempts. Similarly, there are groups of Dominants who wish to co-exist with their sibling species. It also seems that as part of their infiltration techniques, the Dominants suppress the memory of their own agents to avoid compromises in their security should the agent be captured.

Technologically, the Dominants made use of genetic engineering in an attempt to 'convert' the more numerous humans into more Dominants. They also made use of both cloning as well as nanites in order to achieve their goals. They have also been noted to use extensive brain washing techniques on individuals.

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