ATP synthases are unusually complex molecules, which fractionate most readily into two major units, one a water soluble unit called F(1) and the other a detergent soluble unit called F(0). In almost all known species the F(1) unit consists of 5 subunit types in the stoichiometric ratio alpha(3)beta(3)gammadeltaepsilon while the F(0) unit contains 3 subunit types (a, b, and c) in E. coli, and at least 10 subunit types (a, b, c, and others) in higher animals. It is now believed by many investigators that during the synthesis of ATP, protons derived from an electrochemical gradient generated by an electron transport chain are directed through the F(0) unit in such a way as to drive the rotation of the single gamma subunit, which extends from an oligomeric ring of at least 10 c subunits in F(0) through the center of F(1). It is further believed by many that the rotating gamma subunit, by interacting sequentially with the 3 alphabeta pairs of F(1) (360 degrees cycle) in the presence of ADP, P(i), and Mg++, brings about via "power strokes" conformational/binding changes in these subunits that promote the synthesis of ATP and its release on each alphabeta pair. In support of these views, studies in several laboratories either suggest or demonstrate that F(0) consists in part of a proton gradient driven motor while F(1) consists of an ATP hydrolysis driven motor, and that the gamma subunit does rotate during F(1) function. Therefore, current implications are that during ATP synthesis the former motor drives the latter in reverse via the gamma subunit. This would suggest that the process of understanding the mechanism of ATP synthases can be subdivided into three major levels, which include elucidating those chemical and/or biophysical events involved in (1) inducing rotation of the gamma subunit, (2) coupling rotation of this subunit to conformational/binding changes in each of the 3 alphabeta pairs, and (3) forming ATP and water (from ADP, P(i), and Mg(++)) and then releasing these products from each of the 3 catalytic sites. Significantly, it is at the final level of mechanism where the bond breaking/making events of ATP synthesis occur in the transition state, with the former two levels of mechanism setting the stage for this critical payoff event. Nevertheless, in order to get a better grip in this new century on how ATP synthases make ATP and then release it, we must take on the difficult challenge of elucidating each of the three levels of mechanism.