NFAT and NF-kappaB proteins are members of a superfamily of transcription factors whose activity plays a crucial role in the activation, proliferation and apoptosis of lymphocytes. Both types of factors share a number of properties, including similar DNA binding domains and rapid nuclear translocation upon antigenic stimulation. While NF-kappaBs control both innate and adaptive immune responses, NFATs control the adaptive immune system which emerged-in parallel with the appearance of the NFAT family-in jawed fish. However, NFATs and NF-kappaBs differ remarkably in their function. Whereas NFATs support activation-induced cell death (AICD) of T and B cells, NF-kappaB proteins frequently exert a strong anti-apoptotic effect on lymphocytes and other cells. While the anti-apoptotic activity of NF-kappaBs contributes to their oncogenic capacity, the pro-apoptotic activity favors NFATs as tumor suppressors in lymphoid cells.