According to the original receptor occupancy theory proposed by Clark in the 1930s, the percent occupancy of total available receptors by an agonist is linearly related to the response (or effect). However, the first recognition of "receptor reserve" or "spare receptors" mainly by Furchgott and Stephenson in separate studies about two decades ago has profoundly modified the original receptor occupancy theory, that is, the receptor occupancy is not directly proportional to the responses, and the ED50 (or EC50) could be much lower than the equilibrium dissociation constant (Kd). To date, the receptor reserve phenomenon has been characterized in an increasing number of receptor systems. In theory, spare receptors may influence the profile of dose-response (D-R) relationship as well as that of the competitive or noncompetitive antagonism of receptor-mediated drug actions.