Branched chain amino acids (BCAAs) are building blocks for all life-forms. We review here the fundamentals of BCAA metabolism in mammalian physiology. Decades of studies have elicited a deep understanding of biochemical reactions involved in BCAA catabolism. In addition, BCAAs and various catabolic products act as signaling molecules, activating programs ranging from protein synthesis to insulin secretion. How these processes are integrated at an organismal level is less clear. Inborn errors of metabolism highlight the importance of organismal regulation of BCAA physiology. More recently, subtle alterations of BCAA metabolism have been suggested to contribute to numerous prevalent diseases, including diabetes, cancer, and heart failure. Understanding the mechanisms underlying altered BCAA metabolism and how they contribute to disease pathophysiology will keep researchers busy for the foreseeable future.