TRAF2 is an intracellular signal-transducing protein recruited to the TNFR1 and TNFR2 receptors following TNF stimulation. To investigate the physiological role of TRAF2, we generated TRAF2-deficient mice. traf2^−/− mice appeared normal at birth but became progressively runted and died prematurely. Atrophy of the thymus and spleen and depletion of B cell precursors also were observed. Thymocytes and other hematopoietic progenitors were highly sensitive to TNF-induced cell death and serum TNF levels were elevated in these TRAF2-deficient animals. Examination of traf2^−/− cells revealed a severe reduction in TNF-mediated JNK/SAPK activation but a mild effect on NF-κB activation. These results suggest that TRAF2-independent pathways of NF-κB activation exist and that TRAF2 is required for an NF-κB–independent signal that protects against TNF-induced apoptosis.