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The central characters are the Reverend Eric Camden (Stephen Collins), his wife Annie Camden (Catherine Hicks), and their seven children Matt (Barry Watson), Mary (Jessica Biel), Lucy (Beverley Mitchell), Simon (David Gallagher), Ruthie (Mackenzie Rosman) and the twins David (Lorenzo Brino) and Sam (Nikolas Brino). The Reverend Eric Camden is the senior minister of the Glenoak Community Church, whose Protestant denomination is typically never disclosed (with the exception of an episode that was narrated by Simon in Season 8; in a Season 11 episode in which Annie comments on how Protestants can't have a confession; in Season 6 episode 15 when Matt tells Sarah Glass that his father is Protestant).

In at least one episode, the Disciples of Christ denominational logo (St. Andrew cross and chalice) was displayed prominently on the front of the church's pulpit. Many of the church scenes were filmed at First Christian Church (Disciples of Christ) of North Hollywood. Although the logo display was likely unintentional, there appears to be nothing about the Camdens' brand of Christianity that would be negated if they were not a part of the Disciples of Christ. The reason for the display of the Chalice is most likely due to the rental agreement of the church. On the wall hanging left to the pulpit, the church's logo is present (blue logo with a cross/anchor symbol). The church (First Christian Church of North Hollywood), has noted that when the cast was on set, they often went into the church office to observe how church staff really act.

In an earlier online show guide from Warner Brothers Television, the back story for Eric Camden described him as being an Episcopal Priest leading, with his Bishop's permission, a non-denominational church. Some people find this interesting in light of Stephen Collins' real-life attendance at an Episcopal parish in the Pacific Palisades area.

The family originally consisted of five children (Matt, Mary, Lucy, Simon, and Ruthie), but in the third season, Annie gave birth to twins, Sam and David. Three of the children (Matt, Mary and Simon) moved away from home. Simon went to college, and Matt married and pursued his career as a doctor. Nevertheless, the house is always full; Lucy, her husband Kevin, and their daughter Savannah all live in a house behind the Camdens. Frequent house guests also find the Camden house a home of their own. Due to dissatisfaction with the show and her image, Jessica Biel was slowly written out of the show starting in 2000 and, after an appearance on September 22, 2003 she did not appear again until the Season 10 finale on May 8, 2006. On the other hand, Matt and Simon have regularly found themselves involved with the family since they moved out and Simon (David Gallagher) returned for most of the ninth season and the entire tenth season. Both Beverley Mitchell (Lucy) and Mackenzie Rosman (Ruthie) remained with the show for its entire run, with the exception of the first six episodes of the eleventh season, in which Rosman's character was in Scotland.

Each episode deals with a moral lesson or controversial theme that the family handles either directly or indirectly. Some range from the traumatic (e.g., Eric's sister came to visit and the children found out that she was an alcoholic) to the somewhat trivial (e.g., in one episode, every child acquired an addiction, with even Ruthie being addicted to gum). Beyond the moral lesson in each show, there are also longer-running story arcs. The first episode involved Lucy's (lack of) period. In the later seasons, Eric had to deal with his wife entering menopause and his daughter Ruthie needing a training bra. The topics are usually approached from a socially and politically conservative Protestant Christian point of view (devoting almost all of Season 9 to the alleged need not to have pre-marital sex while, however, several pre-marital episodes occur, including a Season 10 episode where Eric mentions that his parents had to marry because his mother became pregnant with him and most recently Ruthie disclosing that she lost her virginity while in Europe over the summer, although it was revealed to be a lie), although the series avoided touching "hot button" issues (i.e. affirmative action, abortion, and homosexuality). A 2004 episode about the importance of voting on election day seemed to suggest that men in the family were voting for incumbent president George W. Bush, while the women were voting for Massachusetts Senator John Kerry, although the script went out of the way to make sure that no mention of either candidate was ever made directly by name, leaving the viewer to decide and the message of the episode simply being "vote, no matter who you vote for". However, in the same episode in which Matt discloses that the family is Protestant, he also discloses to Sarah that his father is a Democrat. Along with the show's family-oriented storyline, this conservative nature has been responsible, in part, for the show's longevity--appealing to an audience who are rarely targeted. This appears to extend even to the question of the denomination of Eric's church ("Reverend Camden", in the vocabulary of the program's producers and writers).

The show is reliant on the very special episode concept, attempting to introduce contemporary social issues to lend greater emotional resonance to episodes. These episodes do in fact lead to high ratings for the show. The January 24, 2005 episode, which featured the birth of Lucy's daughter Savannah, garnered 7.99 million viewers -- the highest WB rating since 2003. Another example included the would-be series finale, now simply known as the Season 10 finale, which scored 7.56 million viewers on May 8, 2006.

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