The NFAT proteins are a family of Ca2+/calcineurin-responsive transcription factors primarily recognized for their central roles in T lymphocyte activation. Recent studies, however, have demonstrated that the vital role of NFAT signaling is by no means restricted to the immune system. NFAT proteins are potent mediators of Ca2+ signals in many mammalian cells and tissues and control, among others, important steps in myogenesis, chondrocyte differentiation and the development of the cardiovascular system. Owing to the broad spectrum of target genes and the fundamental nature of the cellular processes they control, it comes as no surprise that NFAT proteins are increasingly being recognized as central players in the development of a number of very different human malignancies.