Much has been learned about the etiology and pathogenesis of schizophrenia since the term was first used by Eugene Bleuler over a century ago to describe one of the most important forms of major mental illness to affect mankind.Both nature and nurture feature prominently in our understanding of the genesis of the overall risk of developing schizophrenia.We now have a firm grasp of the broad structure of the genetic architecture and several key environmental risk factors have been identified and delineated.However,much of the heritability of schizophrenia remains unexplained and the reported environmental risk factors do not explain all the variances not attributable to genetic risk factors.The biggest problem at present is that our understanding of the causal mechanisms involved is still in its infancy.In this review,we describe the extent and limits of our knowledge of the specific genetic/constitutional and non-genetic/environmental factors that contribute to the overall risk of schizophrenia.We suggest novel methods may be required to understand the almost certainly immensely complex multi-level causal mechanisms that contribute to the generation of the schizophrenia phenotype.