Rel/NF-κB transcription factors are key regulators of immune, inflammatory and acute phase responses and are also implicated in the control of cell proliferation and apoptosis. Remarkable progress has been made in understanding the signal transduction pathways that lead to the activation of Rel/NF-κB factors and the consequent induction of gene expression. Evidence linking deregulated Rel/NF-κB activity to oncogenesis in mammalian systems has emerged in recent years, consistent with the acute oncogenicity of the viral oncoprotein v-Rel in animal models. Chromosomal amplification, overexpression and rearrangement of genes coding for Rel/NF-κB factors have been noted in many human hematopoietic and solid tumors. Persistent nuclear NF-κB activity was also described in several human cancer cell types, as a result of constitutive activation of upstream signaling kinases or mutations inactivating inhibitory IκB subunits. Studies point to a correlation between the activation of cellular gene expression by Rel/NF-κB factors and their participation in the malignant process. Experiments implicating NF-κB in the control of the apoptotic response also support a role in oncogenesis and in the resistance of tumor cells to chemotherapy. This review focuses on the status of the rel, nfkb and ikb genes and their activity in human tumors and their association with the onset or progression of malignancies.