We examined the roles of interleukin‐1 Type I receptor (IL‐1R1) and tumor necrosis factor receptor 1 (TNFR1) in bone metabolism using mice rendered deficient in these receptors by gene targeting. Sections of decalcified paraffin‐embedded calvariae and humeri from 11‐ to 12‐week‐old mice deficient in IL‐1 Type I receptor (IL‐1R1‐/‐) or TNF receptor 1 (TNFR1‐/‐) were examined by histomorphometry. Wild‐type mice (C57BL/6J X 129/J, WILD) served as controls. Interleukin‐6 (IL‐6) production in primary osteoblastic and bone marrow stromal cell cultures in response to parathyroid hormone (PTH, 100 ng/ml), IL‐1α (10 ng/ml), and TNF‐α (10 ng/ml) was also examined. IL‐1R1‐/‐ and TNFR1‐/‐ mice were viable and appeared phenotypically normal. However, the body weights of the IL‐1R1‐/‐ mice were 30% less than WILD, while the TNFR1‐/‐ mice weighed 30% more than WILD mice of equivalent age. Calvariae and humeri of IL‐1R1‐/‐ and TNFR1‐/‐ mice were normal with respect to trabecular bone volume, osteoclast number, osteoclast surface, growth plate widths, and cortical thickness. Receptor deficiency was confirmed by determining the ability of PTH, IL‐1α, and TNF‐α to stimulate IL‐6 in the media of primary calvaria‐derived osteoblastic cell cultures from CD‐1 and cytokine receptor‐deficient mice. After 24 h of treatment, IL‐1α and TNF‐α did not stimulate IL‐6 production in osteoblasts from IL‐1R1‐/‐ and TNFR1‐/‐ mice, respectively. In contrast, PTH increased IL‐6 levels in the cells from all mice. IL‐6 protein levels in bone marrow supernatants and conditioned media from untreated bone marrow stromal cells were undetectable in WILD, IL‐1R1‐/‐, and TNFR1‐/‐ mice. PTH, IL‐1α, and TNF‐α increased IL‐6 mRNA and protein production in the WILD bone marrow stromal cells. In contrast, PTH and TNF‐α increased IL‐6 mRNA and protein levels in IL‐1R1‐/‐ bone marrow stromal cells while IL‐1α had no effect. These findings demonstrate that normal bone development in mice can occur in the absence of IL‐1R1 or TNFR1 expression. (J Bone Miner Res 1996;11:1736‐1744)