Estrogen receptor-related receptor-α (ERRα) is an orphan nuclear receptor with sequence homology to the estrogen receptors, ERα/β, but it does not bind estrogen. However, several recent studies suggest that ERRα not only plays a functional role in osteoblasts but also impinges on the estrogen axis in bone, as it does in at least certain other estrogen target tissues. We summarize here data on ERRα and its cellular and molecular modes of action that have broad implications for considering the potential role of this orphan receptor as a new therapeutic target in osteopenic disorders such as osteoporosis as well as other estrogen-responsive conditions.