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Denise Huxtable (nee Huxtable) (Lisa Bonet), is the second, free-spirited daughter of Cliff and Clair Huxtable. At the beginning of the series, she is sixteen years old, putting her year of birth in 1968. She loves fashion and music, but did not want to attend school to pursue either interest. A two-year stint at Hillman College leads her to Africa, where she meets and marries Navy Lt. Martin Kendall, who has a daughter, Olivia, from a previous relationship. Denise eventually decides to become a special education teacher and makes arrangements to attend Medgar Evers College to this effect, but that idea does not work out as Denise eventually leaves New York again when Martin is posted to Singapore on a long-term assignment. It is revealed in the finale that she is pregnant.

During the first two seasons, Denise was portrayed as a very popular high-schooler, with many friends, who seemingly had a different boyfriend every episode. Along with her constantly fluctuating love life, were her various hairstyles and choices of clothing, which were occasionally made fun of by Cliff. In later seasons, however, she exhibited a more flighty nature, often expressing ideas that left Cliff and Clair greatly puzzled. In Season 3, Denise left home to attend Hillman College, a fictional, historically African-American college, of which her mother, father and grandfather were all alumni. The Cosby Show's producers created a spin-off series, entitled A Different World, which initially dealt with the life of Denise at college. Denise was written out of the series following its inaugural season (which aired concurrently with Season 4 of The Cosby Show), after actress Lisa Bonet became pregnant. Shortly after the start of Season 5, Denise traveled to Africa for a year, where she fell in love with and married Martin Kendall. In the Season 6 premiere, she returned home, shocking her parents with the news of her surprise marriage to a divorced single father. However, Cliff and Clair accepted the couple when they met Olivia, who immediately won their hearts and was welcomed into the family. Denise was featured regularly on The Cosby Show during Seasons 1-3 and 6-7, and on a recurring basis during Seasons 4 and 5.

The character is loosely based upon Cosby's daughter, Erinn, who was approximately the same age as Denise. Additionally, Denise attended Hillman College, whereas Erinn attended Spelman College, the university that Hillman is believed to be modeled after.