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Penelope "Punky" Brewster (played by Soleil Moon Frye) is a warm, funny and bright girl, abandoned by her parents. Punky's father walked out on her family when she was 2. Several years later, Punky was abandoned by her mother who took her to a Chicago supermarket and disappeared. Punky was alone with her only companion, and faithful dog, Brandon. Afterwards, Punky discovered a vacant apartment in a local building.

The building was managed by photographer Henry Warnimont (George Gaynes), an old widower. Punky quickly became friends with Cherie Johnson (Cherie Johnson), a young girl who lived upstairs in Henry's building with her grandmother Betty Johnson (Susie Garrett). Once Henry discovers Punky in the empty apartment adjacent his, he hears her story. The relationship between the two blossoms, despite red tape from social workers, who ultimately rally to Henry's side, and he becomes Punky's foster father, and later adopts her.

Her other friends are geeky Allen Anderson (Casey Ellison) and stuck-up rich girl Margeaux Kramer (Ami Foster).

One of the most memorable episodes was built around the 1986 Space Shuttle Challenger disaster in which Punky hears about the deaths and her dreams of being an astronaut are nearly squashed. In the end, however, her schoolteacher and Henry, along with guest star Buzz Aldrin, both tell her that she should still follow her dreams.

Other memorable episodes[citation needed] include an incident where Cherie gets locked in an old, junked refrigerator during a game of hide-and-seek (she hid in there and couldn't get out, and subsequently passed out from lack of oxygen), and Punky has to perform CPR (which she had just learned at school) to save her life, as well as an episode where Punky wants to buy a bra, where she utters the famous line, "I'm getting boobs!" to a shocked and embarrassed Henry

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Casey Ellison is now living in Indiana and working as a research assistant for Purdue University.