The resorption, formation and maintenance of bone are coordinated by the action of several hormones, growth factors and transcription factors. Recent experiments based on genetically modified mouse models, gene microarrays and pharmacological intervention indicate that the epidermal growth factor receptor (EGFR) system plays important roles in skeletal biology and pathology. This network, including a family of seven growth factors - the EGFR ligands - and the related tyrosine kinase receptors EGFR (ERBB1), ERBB2, ERBB3 and ERBB4, regulates aspects such as proliferation and differentiation of osteoblasts, chondrocytes and osteoclasts, parathyroid hormone-mediated bone formation and cancer metastases in bone. Here, we summarize and discuss the role of the EGFR and its ligands in skeletal biology and pathology.