Cryptococcus neoformans is a common life-threatening human fungal pathogen. The size of cryptococcal cells is typically 5 to 10 μm. Cell enlargement is observed in vivo, producing cells up to 100 μm. These morphological changes in cell size affect pathogenicity via reducing phagocytosis by host mononuclear cells, increasing resistance to oxidative and nitrosative stress, and correlated with reduced penetration of the central nervous system. Cell enlargement is stimulated by coinfection with strains of opposite mating type, and ste3aΔ pheromone receptor mutant strains have reduced cell enlargement. Analysis of DNA content in this novel cell type revealed that these enlarged cells are polyploid, uninucleate, and produced daughter cells in vivo. Two G protein-coupled receptors are important for induction of the titan cell phenotype: the Ste3a pheromone receptor (in mating type a cells) and the Gpr5 protein. Both receptors control titan cell formation though elements of the cAMP/PKA pathway. This conserved signaling pathway in turn mediates its effect on titan cells through the PKA-regulated Rim101 transcription factor. Additional downstream effectors required for titan cell formation include the G1 cyclin Pcl103; the Rho104 GTPase; and two GTPase activating proteins, Gap1 and Cnc1560. These observations support growing models in which the PKA signaling pathway coordinately regulates many virulence-associated phenotypes in diverse human pathogens. In addition, altered host-pathogen interactions during the early stages of pulmonary cryptococcosis were explored. The relationship between titan cell production and phagocytosis is non-linear, where moderate increases in titan cell production result in profound decreases in phagocytosis. Production of titan cells by the wild-type strain can also confer protection to a titan deficient strain, and size alone is sufficient to protect from phagocytosis, however size does not confer protection to normal-sized cells. These data describe titan cell formation, a novel cell morphology, in C. neoformans. Signaling pathway analysis showed that titan cell production is coregulated with the other cryptococcal virulence factors. In addition, titan cells have reduced phagocytosis and can confer protection from phagocytosis to normal-sized cells. These data suggest that titan cell production is a novel virulence factor in C. neoformans.