The calcineurin-CRZ1 signaling pathway is conserved from yeasts to humans, and is involved in survival, tolerance to biotic and abiotic stress conditions, virulence, and drug resistance. The primary target of calcineurin is Crz1p in yeasts and nuclear factor of activated T-cells (NFAT) in mammals. Calcineurin regulates the expression of various genes involved in cell wall regeneration, ionic homeostasis, virulence, and other cellular processes. Another protein called regulator of calcineurin (RCN) also regulates calcineurin functions. This review discusses the structure, functions, and regulations of CRZ1 in fungi and related organisms. We have also discussed the role of CRZ1 in pathogenicity and virulence in fungi, plants, and animals.