Meningitis is a frequent manifestation of infection due to Cryptococcus neoformans and a major cause of increased morbidity in patients with AIDS. Numerous in vitro gene expression and genetic studies of the fungus have predicted a myriad of genes, pathways, and biological processes that may be critical for pathogenesis, and many studies using animal models have supported the role of these processes during infection. However, the relevance of these hypotheses based on in vitro and animal models has often been questioned. A recent study by Chen et al. [Y. Chen, D. L. Toffaletti, J. L. Tenor, A. P. Litvintseva, C. Fang, T. G. Mitchell, T. R. McDonald, K. Nielsen, D. R. Boulware, T. Bicanic, and J. R. Perfect, mBio 5(1):e01087-13, 2014] represents an important step in understanding the cryptococcal response during human infection.