| Amy Sedaris | Jerri Blank |
| Deborah Rush | Sara Blank |
| Carlo Alban | Megawatti Sukharnabhoutri |
| Maria Thayer | Tammi Littlenut |
| Paul Dinello | Mr. Geoffrey Jellineck |
| Stephen Colbert | Mr. Charles ``Chuck'' Noblet |
| Chris Pratt | Brason |
| Elisabeth Harnois | Monica |
| Joseph Cross | Derrick Blank |
| Gregory Hollimon | Principal Blackman |
| Dan Hedaya | Guy Blank |
| Matthew Broderick | Dr. Roger Beekman |
| David Pasquesi | Stew |
| Alexis Dziena | Melissa |
| Ian Holm | Dr. Putney |
| Sarah Jessica Parker | Peggy Callas |
| Allison Janney | Alice |
| Philip Seymour Hoffman | Henry |
| Kristen Johnston | Coach Muffy Divers |
| Justin Theroux | Mr. Carlo Honklin |
Runaway Jerri Blank returns home at the age of 47 ready to pick up where she left off. This means the ex-con and former drug addict is returning to high school as a freshman. Going through adolescent doldrums and temptations is tough enough for any student, but as a middle-aged drug abuser, Jerri discovers her return to education is more challenging than she ever imagined.
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