Each year, opportunistic invasive fungal disease poses a serious threat to the health of over 300,000 million people world-wide and new therapies are needed urgently. During a systemic infection, the opportunistic pathogens, Candida albicans and Cryptococcus neoformans, activate their phosphate signalling (PHO) pathway to allow phosphate acquisition, thus promoting fungal infection. Specifically, we showed that blocking PHO pathway function at the level of transcriptional in C. neoformans drastically reduces both cryptococcal growth in the blood and infection of the central nervous system (CNS) in a mouse infection model (1,2). Transcriptional activation of the PHO pathway is controlled by a cyclin-dependent protein kinase (CDK) complex comprised of the CDK (Pho85), a cyclin (Pho80) and an SPX domain-containing CDK inhibitor (Pho81). SPX domains are common in PHO pathway machinery and are purported to sense and respond to phosphate scarcity by binding the inositol pyrophosphate signalling molecule, IP7. However the exact role of this interaction in the CDK complex is unknown. In eukaryotes including fungi, IP7 is produced by the sequential phosphorylation of IP3 by inositol polyphosphate kinases. Similar to our PHO pathway activation-defective cryptococcal strain, we found that an IP7-deficient strain failed to disseminate to the CNS (3) and was defective in PHO pathway activation, providing evidence of cross talk between the PHO and inositol pyrophosphate signalling pathways. Here we show that IP7 is essential for cryptococcal PHO pathway activation via interaction with the SPX domain of Pho81. Our results reveal that IP7- dependent and -independent functions of Pho81 are important in promoting a disseminated fungal infection.