Signal transduction cascades are utilized by all organisms to convey signals perceived at the cell surface to effectors within the cell. These enzymatic signaling cascades are important in the pathogenesis of many infections, including cryptococcosis. This chapter summarizes the significance and functional interactions involved in the cell wall integrity, phospholipase, and calcineurin signaling pathways for the establishment of Cryptococcus neoformans virulence. The fungal Plc enzymes referred to in this review preferentially hydrolyze phosphatidylinositol (PI)-based substrates within the cryptococcal cell and affect multiple cellular functions, including the secretion of (phospholipase B ) Plb1. It was found that the Plb1 MW could be as high as 125 kDa due to extensive asparagine N-linked glycosylation, which is responsible for at least 30% of the MW of Plb1 and essential for its activity. It was recently demonstrated that PI-PLC1 (Plc1) regulates cryptococcal virulence, acting in part through interactions with the Pkc/Mpk1 cell wall integrity pathway. In contrast to Plcs from higher eukaryotes, Plcs from the parasite Trypanosoma brucei preferentially hydrolyze the glycosylphosphatidylinositol (GPI) anchor of variant surface glycoprotein or GPI biosynthetic intermediates, in addition to PI, but not the phosphorylated intermediates, despite their localization to the peripheral cytoplasmic face of intracellular vesicles. Metabolic labeling studies performed in S. cerevisiae implicated a Plc enzyme and a secondary-acting protease in hydrolysis of the GPI anchor of certain proteins in the plasma membrane, resulting in their subsequent localization in the cell wall. ScPlc1, the only Plc1 in S. cerevisiae, like CnPlc1, lacks a secretory signal leader peptide.