The NF-kappaB/IkappaB signaling pathway is a critical regulator of cell survival, and constitutive activation of NF-kappaB is a crucial step for many types of cancers to escape programmed cell death. Furthermore, chemotherapeutic agents activate NF-kappaB in cancer cells, and this may partially explain the resistance of cancer cells to chemotherapy. The precise mechanism of the anti-apoptotic action of NF-kappaB is not known, but involves the regulation of several cell cycle regulatory and anti-apoptotic genes. We recently demonstrated that NF-kappaB mediated cell survival is absolutely dependent on two GADD45 family members, GADD45alpha and gamma. In line with this, inhibition of NF-kappaB in cancer cells results in GADD45alpha and g dependent induction of apoptosis, JNK activation and inhibition of tumor growth. These findings establish an unambiguous role for the GADD45 family as an essential mediator of cell survival in cancer cells with implications for cancer chemotherapy and novel drug discovery.