The nuclear factor of activated T cells (NFAT) is a novel renoprotective transcription factor in an inactive form in the cytoplasm and an active form in the nucleus. NFAT is expressed in T cells, heart, kidney and lymphocytes. NFAT plays an essential role in inducing apoptosis of renal tubular epithelial cells. NFAT levels have been observed to increase significantly during kidney diseases. Further, downregulation or silencing of endogenous NFAT mitigates kidney diseases. NFAT regulation depends upon the intricate interplay between calcium ions and calcineurin (CaN), thus orchestrating the NFAT/calcineurin signalling pathway. When CaN is activated, it induces dephosphorylation of NFAT and localises the active NFAT into the nucleus, which ultimately leads to inflammation, fibrosis and apoptosis of kidney cells. Further, the global incidence (>
800 million) due to kidney disease imposes a significant economic burden on the healthcare system. Therefore, it is crucial to comprehend the pathways involved in the pathophysiology of kidney diseases to develop targeted interventions. Ongoing studies indicate potential therapies, including anandamide, 11R-VIVIT and maxacalcitol to regulate NFAT levels in kidney disease. The present review discusses the role and regulation of NFAT in the pathogenesis of kidney diseases. This is focused on various preclinical studies that have shown NFAT downregulation as a potential therapeutic strategy against kidney disease setting the foundation for future clinical investigations.