Cryptococcus neoformans is among the most common human pathogenic fungi and the leading cause of fungal meningitis. It consists of two divergent haploid serotypes A and D, as well as their hybrid serotypes AD. Hybridization between the two serotypes A and D is a widespread phenomenon in natural populations of this species. Studies have shown that serotype AD strains possess unique properties in several medically important traits: they are more virulent in animal models, more tolerant to antifungal drugs, more tolerant to UV radiation and other stresses than one or both parental serotypes. Despite the potential medical and evolutionary importance, relatively little is known about the phenotypic and genotypic consequences of the hybridization in C. neoformans. In my thesis, I present a series of studies that show: (1) recombination occurs at a very low frequency during hybridization between serotypes A and D; (2) serotypes A and D in C. neoformans have diverged from each other not only at the DNA sequence level, but also at the chromosomal structure level, both of which contributed to suppressed recombination and limited genetic introgression between the two serotypes; (3) though there is widespread hybridization, the hybrids seemed largely distinct and the genomes of the parental serotypes A and D populations are relatively unaffected by the hybrids in natural populations; and (4) the fixation of these serotype specific chromosomal rearrangements in the two serotypes, together with evidences of selective sweeps observed at both inversion junctions and genes located close to chromosomal inversions suggest that these rearranged regions (or genes surrounding these regions) were likely involved in the diversification between the two serotypes. My studies provide a genetic framework for future quantitative analyses of medically important traits of C. neoformans. / Thesis / Doctor of Philosophy (PhD)