In 1998, Lathan made her film debut with a role opposite Wesley Snipes and Stephen Dorff in the supernatural action film "Blade". In 1999, she would gain recognition for her work in two African-American ensemble films, "The Wood" and "The Best Man". In "The Wood", Lathan played the grown up version of the protagonist's teenage crush turned best friend. Her work in the film was memorable although it didn't afford her much onscreen time. As Robin in "The Best Man", she played the girlfriend of commitment-shy novelist Harper (Taye Diggs), a man bestowed with the title honor in a friend's wedding. Lathan was subtle and insinuating in the role, creating a strong, well-rounded and entirely sympathetic character. That same year she appeared as Eddie Murphy's love interest in the prison buddy comedy "Life". Gina Prince-Bythewood's "Love and Basketball" (2000), a time-spanning look at the growth of a romantic relationship and the development of a star athletes, paired Lathan with "The Wood" co-star Omar Epps, each playing talented basketball players who become childhood friends and come closer through their respective trials to make the big time, ultimately coming to question which of the two titular things is more important. "Love and Basketball" was a challenge for Lathan, who had no real life basketball experience. Tireless training helped her to get to a skill level that would facilitate filming, and the buzz surrounding this well-crafted breakout film propelled the beautiful and talented actress into the spotlight. Later that year, she reteamed with Prince-Bythewood, co-starring in the director's adaptation of Terry McMillan's "Disappearing Acts" (2000), an HBO original film.
In 2002, Lathan reunited with Taye Diggs and the director of "The Wood" (Rick Famuyiwa) to film "Brown Sugar", a romantic comedy that also featured Mos Def. The actress then secured a high profile, breakthrough role opposite Denzell Washington in director Carl Franklin's crime thriller "Out of Time" (2003), playing Washington's high school sweetheart, with whom he becomes embroiled in an adulterous affair. Between film projects, Latham kept busy on the stage, starring opposite Billy Crudup in the New York Shakespeare Festival's Central Park production of "Measure for Measure" in the summer of 2001; and in 2003, she starred opposite Sean Combs and Phyllicia Rashad in the Broadway production of "A Raisin in the Sun," for which she received a Tony nomination for Best Performance by a Featured Actress in a Play. That triumph was immediately followed by a turn as the leader of an archeological expedition caught up in a war between extraterrestrial baddies in the fushion franchise "Alien Vs. Predator" (2004).