Estrogen-related receptor (ERR)γ is an orphan nuclear hormone receptor that belongs to the ERR subfamily of transcription factors. No endogenous ligand has been identified to date. ERRγ possesses ligand-independent transcriptional activity that is regulated by co-regulator interactions, and post-translational modifications (PTMs). Recent data from animal models have established ERRγ as a crucial mediator of multiple endocrine and metabolic signals. ERRγ plays important roles in pathological conditions such as insulin resistance, alcoholic liver injury, and cardiac hypertrophy, and controls energy metabolism in the heart, skeletal muscle, and pancreatic β cells. These findings corroborate the importance of ERRγ in metabolic homeostasis, and suggest that ERRγ is a good target for the treatment of metabolic diseases.