Daphne Rubin-Vega is best known for the roles she originated, including Mimi (RENT) and Conchita (Anna in the Tropics), both of which earned her Tony Award nominations. Other originated roles include Dolores in Empanada Loca, Rahmi in Gum, Sofia in Nilo Cruz' Two Sisters and a Piano, Canary Mary in Suzan-Lori Parks' F-ing A, and Lucy in Jack Goes Boating at The Public. She appeared in the Broadway revivals of A Streetcar Named Desire (Stella), The Rocky Horror Picture Show (Magenta) and Les Miserables (Fantine).

Her film credits include In the Heights, tick, tick... BOOM!, Wild Things, Flawless, and Jack Goes Boating.