Atypical antipsychotic drugs have revolutionized the treatment of schizophrenia and related disorders. The current clinically approved atypical antipsychotic drugs are characterized by having relatively low affinities for D2-dopamine receptors and relatively high affinities for 5-HT2A serotonin receptors (5-HT, 5-hydroxytryptamine (serotonin)). Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug that is reported to be a high-affinity D2-dopamine receptor partial agonist. We now provide a comprehensive pharmacological profile of aripiprazole at a large number of cloned G protein-coupled receptors, transporters, and ion channels. These data reveal a number of interesting and potentially important molecular targets for which aripiprazole has affinity. Aripiprazole has highest affinity for h5-HT2B-, hD2L-, and hD3-dopamine receptors, but also has significant affinity (5–30 nM) for several other 5-HT receptors (5-HT1A, 5-HT2A, 5-HT7), as well as α1A-adrenergic and hH1-histamine receptors. Aripiprazole has less affinity (30–200 nM) for other G protein-coupled receptors, including the 5-HT1D, 5-HT2C, α1B-, α2A-, α2B-, α2C-, β1-, and β2-adrenergic, and H3-histamine receptors. Functionally, aripiprazole is an inverse agonist at 5-HT2B receptors and displays partial agonist actions at 5-HT2A, 5-HT2C, D3, and D4 receptors. Interestingly, we also discovered that the functional actions of aripiprazole at cloned human D2-dopamine receptors are cell-type selective, and that a range of actions (eg agonism, partial agonism, antagonism) at cloned D2-dopamine receptors are possible depending upon the cell type and function examined. This mixture of functional actions at D2-dopamine receptors is consistent with the hypothesis proposed by Lawler et al (1999) that aripiprazole has ‘functionally selective’ actions. Taken together, our results support the hypothesis that the unique actions of aripiprazole in humans are likely a combination of ‘functionally selective’ activation of D2 (and possibly D3)-dopamine receptors, coupled with important interactions with selected other biogenic amine receptors—particularly 5-HT receptor subtypes (5-HT1A, 5-HT2A).