Inositol polyphosphates are a family of secondary messengers in eukaryotes, including fungal pathogens. However, their role in cellular function and pathogenesis remains to be fully elucidated. The opportunistic fungal pathogen, Cryptococcus neoformans, is a common cause of deadly meningoencephalitis, and is an accepted fungal model. Using gene deletion analysis and HPLC, we demonstrated in C. neoformans, that the generation of inositol polyphosphate species with single phosphates (IPs) or dimeric phosphates (pyrophosphates: PP-IPs) on the inositol ring, requires phospholipase C1 (Plc1) to generate IP3, and a series of downstream IP kinases (Arg1, Ipk1, Kcs1, and Asp1) to convert IP3 to IP4-8. Functional disruption of most of the components of the Plc1/IP kinase pathway has a dramatic impact on attenuation of the cryptococcal virulence composite, and on the ability of C. neoformans to disseminate from the primary site of infection (lungs) to the central nervous system in a mouse inhalation model of infection. Some IP kinase mutants also exhibit a reduced rate of phagocytosis by primary monocytes and monocytic cell lines. The contribution of IP and PP-IP species to the cryptococcal virulence composite, and the potential for IP kinases to be used as antifungal drug targets, will be discussed.