Talley was promoted to a main cast member in the credits of The SpongeBob SquarePants Movie. She is married to Tom Kenny, who voices SpongeBob. Aside from Karen, Talley has voiced numerous other characters, such as all of Karen's family members and some of Plankton's cousins. Many episodes feature her voicing machines, loudspeakers, etc. in a similar fashion to Karen's deadpan tone.
Talley makes two live-action cameo appearances in the show. Her first cameo is in "Friend or Foe" as a nauseous customer eating Patchy's food. Her second is as a soap opera actress that Karen watches in "King Plankton."
Talley's father was a firefighter and she lived in Chicago near Chicago Midway International Airport during her childhood. In her twenties, she performed improv comedy in Chicago at the Improv Institute and The Second City. She married Tom Kenny in 1995, and she currently resides in Studio City with her husband and their two children, Mack and Nora.