H⁺-ATP synthase (F₁F_o ATPase) catalyzes the synthesis and/or hydrolysis of ATP, and the reactions are strongly affected by all the substrates (products) in a way clearly distinct from that expected of a simple reversibly operating enzyme. Recent studies have revealed the structure of F₁, which is ideally suited for the alternating binding change mechanism, with a rotating γ-subunit as the energy-driven coupling device. According to this mechanism ATP, ADP, inorganic phosphate (P_i) and Mg²⁺ participate in the forward and reverse overall reactions exclusively as the substrates and products. However, both F₁ and F₁F_o demonstrate non-trivial steady-state and pre-steady-state kinetics as a function of variable substrate (product) concentrations. Several effectors cause unidirectional inhibition or activation of the enzyme. When considered separately, the unidirectional effects of ADP, P_i, Mg²⁺ and energy supply on ATP synthesis or hydrolysis may possibly be explained by very complex kinetic schemes; taken together, the results suggest that different conformational states of the enzyme operate in the ATP hydrolase and ATP synthase reactions. A possible mechanism for an energy-dependent switch between the two states of F₁F_o ATPase is proposed.