Concern is building about high rates of schizophrenia in large cities, and among immigrants, cannabis users, and traumatized individuals, some of which likely reflects the causal influence of environmental exposures. This, in combination with very slow progress in the area of molecular genetics, has generated interest in more complicated models of schizophrenia etiology that explicitly posit gene-environment interactions (EU-GEI. European Network of Schizophrenia Networks for the Study of Gene Environment Interactions. Schizophrenia aetiology: do gene-environment interactions hold the key? [published online ahead of print April 25, 2008] Schizophr Res; S0920-9964(08) 00170-9). Although findings of epidemiological gene-environment interaction (G x E) studies are suggestive of widespread gene-environment interactions in the etiology of schizophrenia, numerous challenges remain. For example, attempts to identify gene-environment interactions cannot be equated with molecular genetic studies with a few putative environmental variables "thrown in": G x E is a multidisciplinary exercise involving epidemiology, psychology, psychiatry, neuroscience, neuroimaging, pharmacology, biostatistics, and genetics. Epidemiological G x E studies using indirect measures of genetic risk in genetically sensitive designs have the advantage that they are able to model the net, albeit nonspecific, genetic load. In studies using direct molecular measures of genetic variation, a hypothesis-driven approach postulating synergistic effects between genes and environment impacting on a final common pathway, such as "sensitization" of mesolimbic dopamine neurotransmission, while simplistic, may provide initial focus and protection against the numerous false-positive and false-negative results that these investigations engender. Experimental ecogenetic approaches with randomized assignment may help to overcome some of the limitations of observational studies and allow for the additional elucidation of underlying mechanisms using a combination of functional enviromics and functional genomics.