Virulence in the human fungal pathogen Cryptococcus neoformans is associated with the α mating type. Studies to identify the properties of α cells that enhance pathogenesis have led to the identification of a mating-type locus of unusually large size and distinct architecture. Here, we demonstrate that the previously identified MATα components are insufficient to regulate sexual differentiation, and we identify a novel α-specific regulator,SXI1α. Our data show that SXI1α establishes α cell identity and controls progression through the sexual cycle, and we discover that ectopic expression of SXI1α in a cells is sufficient to drive a/α sexual development. SXI1α is the first example of a key regulator of cell identity and sexual differentiation in C. neoformans, and its identification and characterization lead to a new model of how cell fate and the sexual cycle are controlled in C. neoformans.