The transcription factor NF-κB was discovered in 1986 and since then has been extensively studied in relation to cancer research and inflammatory or autoimmune diseases due to its important roles in the regulation of apoptosis and inflammation as well as innate and adaptive immunity. Although much is known about NF-κB signaling, novel NF-κB functions in different diseases are still being uncovered, together with its target proteins, interaction partners and regulators of its activation cascade. Proteomic approaches are particularly suited to the discovery of new proteins involved in distinct signal transduction cascades. This review provides an update on and extension of a recent review that summarized a number of proteomic approaches to NF-κB signaling. The studies discussed here utilized innovative techniques and offer several new hypotheses on the role of NF-κB in physiological and pathophysiological processes, which open new avenues for research on NF-κB in the future.