The interaction of pathogenic Cryptococcus species with their various hosts is somewhat unique compared to other fungal pathogens such as Aspergillus fumigatus and Candida albicans. Cryptococcus shares an intimate association with host immune cells, leading to enhanced intracellular growth. Furthermore, unlike most other fungal pathogens, the signs and symptoms of cryptococcal disease are typically self-inflicted by the host during the host's attempt to clear this invader from sensitive organ systems such as the central nervous system. In this review, we will summarize the story of host-Cryptococcus interactions to date and explore strategies to exploit the current knowledge for treatment of cryptococcal infections.