There is strong evidence to suggest that genetic variation plays an important role in inter-individual differences in medication response and toxicity. Most of the previous pharmacogenetic studies, however, cannot be reconfirmed. Of note, drug efficacy or side effects depend not only on genetic factors but also on nongenetic factors, such as illness duration, past treatment history, and drug dosage or blood concentration. However, most pharmacogeneticists did not consider or control the possible impact of the nongenetic factors. Schizophrenia is a severe neuropsychiatric disorder with a polygenic mode of inheritance that is also governed by nongenetic factors. Schizophrenia's symptoms are principally subdivided into two subtypes, positive and negative. The positive symptoms include delusions and hallucinations; the negative symptoms, blunted affect and social withdrawal. Atypical antipsychotics are usually superior in the treatment of negative symptoms than typical agents. Although atypical agents are becoming the mainstay for schizophrenia treatment, what makes an antipsychotic “atypical” remains unclear. One of our recent studies have simultaneously evaluated the effects of genetic and nongenetic determinants on the efficacy of risperidone (a widely used atypical antipsychotic agent). We found that 5-HT2A receptor 102-T/C polymorphism could predict clinical response (mainly for negative symptoms rather than positive symptoms) in schizophrenia. Among nongenetic factors, fewer previous hospitalizations and higher risperidone dosage also predicted better treatment response after control for the 102-T/C polymorphism and other confounders. It is hoped that this novel study model could revolutionize future research in pharmacogenetics or other fields of genetics. Drug Dev. Res. 60:164–171, 2003.