NF-κB family transcription factors are a common downstream target for inducible transcription mediated by many different cell-surface receptors, especially those receptors involved in inflammation and adaptive immunity. It is now clear that different classes of receptors employ different proximal signaling strategies to activate the common NF-κB signaling components, such as the IKK complex. For antigen receptors expressed by T and B cells, this pathway requires a complex of proteins including the proteins Carma1, Bcl10, and Malt1. Here, we discuss some of what is known about regulation of these proteins downstream of TCR/CD3 and co-stimulatory CD28 signaling. We also discuss another unique aspect of TCR-mediated NF-κB activation, i.e., the spatial restriction imposed on signaling events by the formation of the immunological synapse between a T cell and antigen-presenting cell presenting specific peptide/MHC.