Calcineurin is a serine-threonine protein phosphatase that plays a pivotal role in a wide series of crucial physiologic processes such as T-cell activation, apoptosis, skeletal myocyte differentiation, and cardiac hypertrophy. A new family of regulators of calcineurin (RCANs) has been shown to modulate calcineurin activity through direct binding of it in vivo. Calcineurindependent signals are transduced to the nucleus by nuclear factor of activated T-cells (NFAT) transcription factors that undergo nuclear translocation upon dephosphorylation and promote transcriptional activation of target genes. The recent researches have revealed that RCAN1 modulating catalytic activity of calcineurin can function as an endogenous backfeed inhibitor during the calcineurin-NFAT signalling pathway. RCANs have now been implicated in several pathological conditions including Alzheimer’s disease, down syndrome and cardiac hypertrophy. In addition, the RCAN family is a rational, functional name for RCAN gene and it is proposed in 2007. It is, therefore, necessary to review the RCAN gene, RCANs and the roles of RCANs in a wide variety of diseases especially including Alzheimer’s disease. It is suggested that regulation of RCAN expression may be a new target on neurodegeneration disease.