TRAF3 was found as a protein that binds to the cytoplasmic tail of CD40 but is part of a family of proteins with common structure and activity. To clarify the physiological roles of TRAF3, we introduced a TRAF3 null mutation in mice through homologous recombination. TRAF3-deficient mice appear normal at birth but become progressively runted, correlating with progressive hypoglycemia and depletion of peripheral white cells. The mutant mice die by 10 days of age. Fetal liver cells from TRAF3-deficient embryos can reconstitute all hematopoietic lineages in lethally irradiated mice. However, these reconstituted mice are impaired in their immune responses to T-dependent antigen, and their T cells are functionally defective. These findings indicate that TRAF3 is required for postnatal development and for a competent immune system.