In this study, we show that Nfat1, Nfat2 and Nfat4 are critical effectors of calcineurin in T-ALL that act mostly in a redundant fashion in regulating leukemia initiating potential and the expression of several genes/pathways that could mediate the pro-oncogenic properties of Cn/NFAT activation. This evidence concerns the gene NFATC3 and acute lymphoblastic leukemia.