Hybridization refers to mating between species or between genetically differentiated populations of the same species. Although hybrid offspring may exhibit sterility and/or inviability, hybridization can generate novel genotypic and phenotypic diversities, leading to the origin of new traits and new species, the expansion into ecological niches outside of the parental range (e.g., host range), and altered virulence properties in pathogens. However, the relationship between parental genetic divergence and hybrid performance remains largely unknown. The human pathogenic Cryptococcus (HPC) is an ideal model to study the impacts of parental divergence on the genetic and phenotypic consequences of hybridization. HPC consists of a group of divergent lineages with various degrees of interfertility. These yeasts are the etiologic agents of cryptococcosis, a potentially lethal disease in humans and animals. In this thesis, I examined the effects of parental divergence on cryptococcal hybrids from multiple aspects. I conducted genetic crosses between different lineages to evaluate the mating success and the germination of sexual spores (i.e., basidiospores) under various environmental conditions. Then, I investigated the genotypic and phenotypic diversities among the hybrids under different environmental conditions. Furthermore, I examined the genome stability of diploid inter-lineage hybrids through laboratory experimental evolution and the effect of antifungal drug stress on the loss of heterozygosity (LOH) in these hybrids. We found that parental genetic divergence plays an important role in genotypic and phenotypic diversities among hybrid progeny in HPC. However, our results indicate that parental genetic di-vergence alone can’t explain most of the observed variations. Instead, genetic divergence along with specific parental strains, environmental factors, and their interactions all contributed to hybridization success and to hybrid genotypic and phenotypic variations. My findings will broaden the current understanding of the phenotypic and genotypic consequences of hybridization and explore the connection between genetic architecture and hybrid speciation in the human pathogenic Cryptococcus. / Thesis / Doctor of Science (PhD) / The role of hybridization in evolution can vary widely, giving rise to hybrid vigor and hybrid weakness. Hybridization plays an important role in plants and animals, especially crops, with advantages of increased yield and quality of products. However, the emergence of hybrid vigor in pathogens with increased virulence is an increasing threat to plant, animal, and human healths. My PhD thesis aimed at understanding the effects of parental divergence on hybridization and hybrids in the human pathogenic Cryptococcus. Here, I investigated basidiospore germination rate and hybrid progeny genotypes and phenotypes from diverse genetic crosses in this group of pathogens. My findings contribute towards understanding cryptococcal hybrids and establishing treatment plans against infections by these hybrids.