There is credible evidence that environmental factors influence individual risk and/or severity of autism spectrum disorders (hereafter referred to as autism). While it is likely that environmental chemicals contribute to the etiology of autism via multiple mechanisms, identifying specific environmental factors that confer risk for autism and understanding how they contribute to the etiology of autism has been challenging, in part because the influence of environmental chemicals likely varies depending on the genetic substrate of the exposed individual. Current research efforts are focused on elucidating the mechanisms by which environmental chemicals interact with autism genetic susceptibilities to adversely impact neurodevelopment. The goal is to not only generate insights regarding the pathophysiology of autism, but also inform the development of screening platforms to identify specific environmental factors and gene×environment (G×E) interactions that modify autism risk. Data from such studies are needed to support development of intervention strategies for mitigating the burden of this neurodevelopmental condition on individuals, their families and society. In this review, we discuss environmental chemicals identified as putative autism risk factors and proposed mechanisms by which G×E interactions influence autism risk and/or severity using polychlorinated biphenyls (PCBs) as an example.