Heterogeneity has been a consistent problem in the research and treatment of schizophrenia. Despite marked variation in the onset, phenomenology, treatment response and outcome of schizophrenic patients, our ability to identify subtypes is remarkably limited. A major problem in schizophrenia research has been the use of cross-sectional study designs and heterogeneous patient samples at different stages of the illness and who have been previously exposed to neuroleptics which have potentially confounding effects on the disease. This study intends to identify biologic correlates of the phenomenology and course of schizophrenia by using a prospective, longitudinal, repeated measures design assessing biologic and clinical parameters including measures of psychopathology, side effects, and social adjustment to examine clinical variables of treatment response, illness course, and outcome; measures of central nervous system dopamine activity and brain morphology in patients, from the onset of their illness. Patients were ascertained at hospital admission and assessed with a battery of clinical, neuropsychologic, and biologic measures before undergoing standardized treatment for the acute and maintenance phases of the illness. Upon completion, approximately 120 first-episode patients will have entered the study and will have been followed prospectively for up to 5 years and assessed at specific time intervals. Preliminary results reveal significant abnormalities in brain morphology, growth hormone secretion, eye movement function, and psychotogenic response to dopamine agonists in first-episode, treatment-naive patients which are associated with treatment response and outcome. This article describes the study's rationale, design, and methods, and a summary of the published results to date. These are discussed in terms of their significance for putative clinical subtypes and pathophysiological models of schizophrenia.