The mitochondrial ATP synthase/ATPase (F0F1 ATPase) is perhaps the most complex enzyme known. In animal systems it consists of a minimum of 11 different polypeptide chains, 10 (or more) of which appear to be essential for function, and 1 called the "ATPase inhibitor peptide" which is involved in regulation. Recent studies from a variety of laboratories indicate that the ATP synthase/ATPase complex is regulated by several interrelated factors including the thermodynamic poise of the proton gradient across the inner mitochondrial membrane; the ATPase inhibitor peptide; ADP (and/or ADP and Pi); divalent cations; and perhaps the redox state of SH groups on the F1 molecule. The central focus of this review is the ATPase inhibitor peptide. A model involving four distinct conformational states of F1 seems essential to account for the inhibitor's mode of action. The model depicts the ATPase inhibitor protein as acting at the asymmetric center of the F1 moiety. In addition, it accounts for the "unidirectional" role of the inhibitor peptide as a "down regulator" of ATP hydrolysis and for its binding/debinding dependence on the proton motive force and other regulatory factors. Finally, it is suggested that during any physiological process, where there is an energy demand followed by a resting phase, the F1 molecule may follow a "cyclic" path involving the four distinct conformational states of the enzyme.