This chapter discusses the ability of the pathogenic cryptococci to proliferate intracellularly and examines the different strategies cryptococci use to exit host cells. The intracellular location provides a dual benefit to Cryptococcus, both in avoiding extracellular host immune mechanisms, such as complement, and in reducing exposure to antifungal agents. The establishment of different in vitro systems that utilize cell lines and the application of techniques such as live cell imaging have contributed to rapid advances in one's understanding of the molecular mechanisms influencing Cryptococcus's ability to proliferate intracellularly. Intracellular parasitism is associated with a continuous struggle between the pathogen and its host cell. Within host cells, Cryptococcus encounters a harsh environment of reactive oxygen and nitrogen species; oxygen, nutrient, and metal ion deprivation; and low pH and high temperatures. Therefore, the yeast expresses multiple virulence factors including a capsule, melanin, and a variety of secreted enzymes that can modify the host's defense mechanisms to achieve intracellular replication. The melanized Cryptococcus neoformans strain 145 is more resistant to cell death caused by lymphocytes than the less melanized strain 52. Resistance to cryptococcal infection is associated with a Th1 response and the consequent phagocyte activation, whereas Th2-polarized host responses lead to inhibition of phagocyte activity and enhanced susceptibility to C. neoformans. Whole-genome microarray analysis has identified a large number of candidate genes that may influence proliferative capacity and revealed an unexpected role for mitochondrial genes in regulating cryptococcal hypervirulence in the Vancouver Island strains.