Genetic research on schizophrenia, a common psychiatric disease with complex   etiology and high (56-80%) heritability, has failed to identify causal genes, variants  or causative mechanisms. Given the extensive effort and limited success to date, it is
imperative to review potential reasons for this missing heritability. We argue that a  successful elucidation of hereditary mechanisms in schizophrenia will likely involve   attention to the role of neurodevelopment and cell differentiation and consideration   of the genome structure, including temporal and spatial patterns. The identification  of discrete endophenotypes, the,accommodation of environmental effects at the  level of gene expression, including any sex differences and patterns of mutations,  including de novo events, and the use of analytic techniques that go beyond genomewide association studies. Identification of the heritable component of schizophrenia  is needed to understand the cause of the disorder and to facilitate the development of   effective corrective and possibly preventive measures.