Invasive fungal diseases cause more than 1.5 million deaths each year. The essential nutrient, phosphate, is critical for invasive fungal pathogens to cause disease. Phosphate levels are regulated by the PHO pathway, which consists of a CDK complex: the Pho85 kinase, the Pho80 cyclin and the CDK inhibitor Pho81. We and others have shown that phosphate deficiency achieved by blocking the activation of the phosphate acquisition (PHO) pathway, attenuates disseminated infection in mouse models of candidiasis and cryptococcosis. By creating a Pho80 cyclin mutant (pho80Δ), we now demonstrate that constitutively elevating phosphate in Cryptococcus neoformans also abrogates pathogenicity. To investigate the impact of elevated phosphate on cellular function, we compare the transcriptomes of WT and pho80Δ using RNAseq and use the data to select a range of conditions to test pho80Δ growth. The results demonstrate that pho80Δ accumulates metal ions, including calcium, has compromised mitochondrial function and ER stress response and is sensitive to inhibitors of the energy-sensing TOR pathway and inhibitors of the Ca2+-dependent phosphatase, calcineurin. The calcineurin pathway promotes growth during heat, ER, and oxidative stress. Phosphate deprivation rescues pho80Δ sensitivity to both TOR and calcineurin inhibition, suggesting that excess phosphate or excess phosphate-cation complexes are cytotoxic and that the calcineurin and TOR pathways are essential for mitigating the stress associated with phosphate overload, especially at 37°C. Using fluorescent reporter strains, we also demonstrate that the calcineurin pathway is activated not only by heat stress, but also by phosphate deprivation; and that the calcineurin response is reduced in the phosphate-rich pho80Δ mutant. Our data provide novel mechanistic insight into how calcineurin pathway activation is critical for alleviating the stress associated with phosphate overload.