The importance of the IkappaB kinase (IKK)/NF-kappaB signaling pathway in immunoregulatory functions is well accepted. However, the relevance of IKK and NF-kappaB in tumor maintenance, tumor promotion and possibly even in tumor initiation is becoming more evident. Activation of the IKK/NF-kappaB signaling pathway leads to the induction of target genes that can interfere with apoptosis, cell cycle regulation, cell invasion and metastatic growth as well as radio- and chemotherapy. By possibly bridging inflammation and cancer NF-kappaB might also contribute to tumorigenesis. Several natural compounds and synthetic drugs that are able to inhibit the IKK/NF-kappaB activation pathway have been shown to either prevent cancer or to inhibit cell growth in animal models. However, these compounds do not selectively inhibit any of the NF-kappaB activation pathways. Furthermore, general inhibition of NF-kappaB might lead to immunodeficiency. The investigation of the different NF-kappaB signaling pathways in different cell types and their role in certain diseases is therefore needed to evaluate the most successful therapeutic strategies.