Calcineurin (CaN) is a unique calcium (Ca²⁺) and calmodulin (CaM)-dependent serine/threonine phosphatase that becomes activated in the presence of increased intracellular Ca²⁺ level. CaN then functions to dephosphorylate target substrates including various transcription factors, receptors, and channels. Once activated, the CaN signaling pathway participates in the development of multiple organs as well as the onset and progression of various diseases via regulation of different cellular processes. Here, we review current literature regarding the structural and functional properties of CaN, highlighting its crucial role in the development and pathogenesis of immune system disorders, neurodegenerative diseases, kidney disease, cardiomyopathy and cancer.