For currently available antipsychotic drugs, blockade of dopamine D(2) receptors is a critical component for achieving antipsychotic efficacy, but it is also a driving factor in the development of extrapyramidal symptoms (EPS). To inform the clinical development of asenapine, generic mathematical models have been developed for predicting antipsychotic efficacy and EPS tolerability based on D(2) receptor occupancy. Clinical data on pharmacokinetics, D(2) receptor occupancy, efficacy, and EPS for several antipsychotics were collected from the public domain. Asenapine data were obtained from in-house trials. D(2) receptor occupancy data were restricted to published positron emission tomography studies that included blood sampling for pharmacokinetics. Clinical efficacy data were restricted to group mean endpoint data from short-term placebo-controlled trials, whereas EPS evaluation also included some non-placebo-controlled trials. A generally applicable model connecting antipsychotic dose, pharmacokinetics, D(2) receptor occupancy, Positive and Negative Syndrome Scale (PANSS) response, and effect on Simpson-Angus Scale (SAS) was then developed. The empirical models describing the D(2)-PANSS and D(2)-SAS relationships were used successfully to aid dose selection for asenapine phase II and III trials. A broader use can be envisaged as a dose selection tool for new antipsychotics with D(2) antagonist properties in the treatment of schizophrenia.