The nuclear factor (NF)-κB pathway is important for the expression of a wide variety of genes that are involved in the control of the host immune and inflammatory response, and in the regulation of cellular proliferation and survival. The constitutive activation of this pathway is associated with inflammatory and autoimmune diseases, such as asthma, rheumatoid arthritis and inflammatory bowel disease, in addition to atherosclerosis, Alzheimer's disease, cancer and diabetes. One of the key steps in activating the NF-κB pathway is the stimulation of the IκB (inhibitor of κB) kinases. Recent data indicate that these kinases activate the NF-κB pathway through distinct steps that are operative in both the cytoplasm and the nucleus. A better understanding of the mechanisms that activate this pathway provides the potential for defining new therapeutic targets that might prevent the aberrant activation of NF-κB in a variety of human diseases.