Progress in identifying susceptibility genes for psychiatric disorders has been hindered by non-Mendelian transmission patterns, probable genetic heterogeneity, and an inability to detect premorbid and non-penetrant carriers of predisposing genes. In addition, evidence suggests that some susceptibility loci may be shared among conditions traditionally viewed as etiologically distinct. More recently, schizophrenia and other complex diseases have been reconceptualized as sets of quantitative traits that reflect intermediate phenotypes between predisposing genes and symptomatic expression. This symposium addresses recent progress toward achieving a mechanistic understanding of specific gene disruption in schizophrenia. We highlight recent translational work specifying the effects of sequence variations in genes associated with schizophrenia across the cognitive, anatomical, physiologic, cellular, and molecular levels and determining whether these genotype-phenotype relationships are paralleled in mice with experimentally induced alterations of these genes. We also discuss how the use of multiple manipulations of the same gene and an inducible transgene platform may facilitate isolating critical regions of genes that will aid in the identification of functional polymorphisms in humans. The focus will be on the Disrupted in Schizophrenia 1 (DISC1) gene, but work extending this approach to other putative susceptibility loci, such as dysbindin, will be included.