The manifest clinical heterogeneity of schizophrenia, combined with the failure, to date, to demonstrate the existence of a unitary disease process, has led to the conceptualization of schizophrenia as a pathophysiologically heterogeneous disorder. Various approaches have been developed to define homogeneous subgroups of schizophrenic patients. An alternative approach to the use of multiple criteria for defining putative disease entities is the use of specific sign and symptom complexes, or domains of psychopathology, for reducing heterogeneity. There is now considerable evidence supporting the separation of schizophrenic symptoms into three domains: hallucinations and delusions, thought disorder, and deficit symptoms. The conceptual evolution and validating evidence for this approach are reviewed, and an illustration of how the domains of psychopathology are applied in schizophrenia research is presented.