Recent advances in transgenic and gene-targeting approaches, mouse genetics, and microsurgical technology are initiating a revolution that has led to the unexpected coupling of in vivo molecular physiology with genetically engineered mice (for a brief review, see references 1, 2). This perspective covers problems and prospects for using the engineered mouse as a model system to dissect complex, in vivo physiological traits, using the cardiovascular system as a paradigm for other complex organ systems (eg, pulmonary, gastrointestinal, neural, and renal).