Schizophrenia is a complex disorder, whose phenotypic variation and likely extensive genetic heterogeneity is not adequately captured by current clinical classifications. Despite a century of research, the field abounds in inconsistent empirical findings and conceptual controversies. How far can genetics take us in understanding its causes and what is the role of the environment? Is the disorder rooted in neurodevelop-ment or in neurodegeneration? Can we bridge the gap between the objective measurement of brain function and the subjective phenomenology of schizophrenia? These, and other unresolved fundamental issues, lead to questions about the status of schizophrenia as a putative disease entity and to attempts at its “decon-struction” by using intermediate (endo-) phenotypes. Endophenotypes are objectively measurable, biologically anchored heritable traits, which co-segregate with clinical illness in pedigrees and may also be expressed in clinically unaffected family members. This chapter reviews the phenotypic variation and likely etiological heterogeneity underlying the clinical phenotype of schizophrenia; outlines the conceptual foundation and criteria for the application of endophe-notype research strategies; and provides an overview of promising endophenotype-based approaches including measures of cognition, electrophysiological brain responses, and brain imaging techniques. The design and findings of the Western Australian Family Study of Schizophrenia provide an illustrative example of the application of an endophenotype approach to parsing the complexity of the disorder with a view to facilitating its genetic analysis.