A major regulator of lymphocyte survival and activation is the transcription factor nuclear factor-kappaB (NF-kappaB). Controlled activation of NF-kappaB is essential for the immune and inflammatory response as well as for cell proliferation and protection against apoptosis. The NEMO/IkappaB kinase (IKK) complex is the central integrator of most stimuli leading to NF-kappaB activation, but a detailed knowledge of the upstream events is available only for a limited number of stimuli. In particular, although most players have probably been identified, relatively little is known about the detailed molecular mechanisms involved in the cascade leading to NF-kappaB activation following engagement of the T-cell receptor by a foreign antigen. In this review, we discuss recent insights into this specific signal transduction cascade, and the way it is controlled both spatially and temporally.