Ironically, the development of antipsychotics has come full circle (Figure 1 and Table 1). The first wave of effective antipsychotics was serendipitously discovered in the 1950s and had multiple mechanisms of action.4-5 The second wave (e.g., haloperidol) was rationally developed to have a specific and selective mechanism of action -- dopamine D2 receptor blockade.5 The third wave completed the circle in that the newest antipsychotics also have multiple mechanisms of action; specifically, they combine blockade of certain subtypes of serotonin (5hydroxytryptamine, 5-HT) receptors and blockade of the D2 receptor. In contrast to the first wave, the third wave was rationally designed to have multiple mechanisms of action. This mini-series of columns will present the historical reasons behind this full circle phenomenon and discuss how it reflects the development process in the pre-HGP era.