Mice rendered null for the genes encoding receptor activator of nuclear factor κB ligand (RANKL) or its receptor, RANK, are osteopetrotic because of failure of osteoclast development. The failure of lactation owing to the lack of development of lobulo-alveolar structures during pregnancy, despite earlier stages of mammary gland development being normal, is now added to each of these phenotypes. The breast phenotype in RANKL-/- (but not in RANK-/-) mice is rescued by treatment of pregnant mice with RANKL-/- indicating a key role for these tumour necrosis factor (TNF) ligand and receptor family members in a crucial terminal step in breast development and lactation. Both RANKL and RANK are synthesized by mammary epithelial cells, with both prolactin and parathyroid hormone-related protein (PTHrP) able to enhance production of mRNA for RANKL. These findings reveal a paracrine-autocrine system in lactation control, with novel signalling pathways that reflect intercellular communication processes in bone.