Life-threatening meningoencephalitis caused by the fungal pathogen Cryptococcus neoformans is difficult to treat, with limited antifungals available and prolonged treatment times that commonly last for months. Relapse is common, extending this treatment time even further. During its lengthy time in the hostile host environment, mutations in C. neoformans that confer enhanced virulence can be selected for. One class of mutations that fall in this category are in a genes that encode components of the SAGA transcriptional coactivator complex, a multiprotein structure that plays a key role in stress response through histone acetylation and deubiquitination. We previously found that clinical strain mutations in the histone acetylation module protein Sgf29 conferred hypervirulence, and that an equivalent mutation was present in the type strain subculture employed by many groups. With further analysis of SAGA we have identified proteins whose loss result in hypovirulence, but also others that contribute to the hypervirulence phenotype. Together, these findings are revealing how SAGA modulates multiple pathways that directly affect virulence and survival in C. neoformans, and are providing deeper insight into the importance of the enzymatic and non-enzymatic components of the SAGA complex.