To define the normal physiological role for the TRAIL/Apo2L in vivo, we generated TRAIL/Apo2L gene‐targeted mice. These mice develop normally and show no defects in lymphoid or myeloid cell homeostasis or function. Although TRAIL/Apo2L kills transformed cells in vitro, TRAIL/Apo2L^–/– mice do not spontaneously develop overt tumors at an early age. However, in the A20 B cell lymphoma‐transferred tumor model, TRAIL/Apo2L^–/– mice are clearly more susceptible to death from overwhelming tumor burden, due to increased lymphoma load in the liver. A20 tumors are susceptible to TRAIL/Apo2L killing in vitro, indicating that TRAIL/Apo2L may act directly to control A20 cells in vivo. Despite the fact that TRAIL binds osteoprotegerin and osteoprotegerin‐transgenic mice are osteopetrotic, TRAIL/Apo2L^–/– mice show no evidence of altered gross bone density, and no alterations in frequency or in vitro differentiationof bone marrow precursor osteoclasts. Moreover, leucine zipper TRAIL has no toxicity when repeatedly administered to osteoprotegerin^–/– mice. Thus, TRAIL/Apo2L is important in controlling tumors in vivo, but is not an essential regulator of osteoprotegerin‐mediated biology, under normal physiological conditions.