Cryptococcus neoformans is a facultative intracellular pathogen responsible for fungal meningoencephalitis primarily in immunocompromised individuals. It has become evident the pathogenicity of C. neoformans is dependent on the fungal cell’s environment. The differential expression of virulence factors, based on the cell’s environmental conditions, is one mechanism allowing for the environmental control of the pathogenic ability of C. neoformans. Here, we discuss how these virulence factors (including melanin, the polysaccharide capsule, and Antiphagocytic protein 1) have been shown to be differentially expressed dependent on the cell’s environment. The genetics and signaling pathways leading to the environmental-dependent regulation of virulence factors will also be examined. Susceptibility to antifungal therapeutics is also regulated by the environment, and thus affects the pathogenic abilities of C. neoformans and disease outcomes. This review will also examine the role of the C. neoformans’s environment on antifungal susceptibilities, and the genetics and signaling pathways responsible for these susceptibility alterations. By examining the complex interplay between the environment and the pathogenicity of C. neoformans, we have a better understanding of the intricacies of the pathogen–environment interaction and how to exploit this interaction to develop the most effective treatment protocols.