Recent studies using genetically modified mice, pharmacological approaches, and human samples have highlighted an important role for the epidermal growth factor receptor (EGFR), selected ligands, and downstream components in endochondral bone formation and joint homeostasis. Although most data demonstrate an important function of this pathway in endochondral ossification and articular cartilage growth, conflicting results on its role in osteoarthritis have been reported. In some contexts, inactivation of EGFR signaling has been shown to protect joints from surgically induced osteoarthritis, whereas in others, similar manipulations worsened joint pathology. The current review summarizes recent studies of cartilage EGFR signaling in long bone development and diseases, provides potential explanations for the reported discrepancies, and suggests directions for future work to clarify the potential of this pathway as target for osteoarthritis treatment. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.