Discovering the genetic basis of idiopathic autism spectrum disorder has been challenging. Recently, new genomic approaches leveraging exome sequencing have identified large numbers of new candidate genes based on new or “de novo” mutations in families with a single affected child, so called simplex families. Even with the likelihood of hundreds of genes involved, many genes are now moving beyond candidates to bona fide risk factors for autism. Detailed analysis of genetically defined autism subtypes may revolutionize our understanding of the disorder and provide significant targets for interventions. In this session, the results of the complete sequencing of the Simons Simplex Collection, ~2,500 families will be presented. The roles of different mutation types and classes of genes will be addressed, as well as how roles may differ in boys and girls with autism. We will also explore how novel biomolecular modules relevant to autism are being discovered using emerging data from the developing brain and new computational approaches. These potentially link many risk genes together into common pathways. Finally, the session will end with detailed discussions of two new genetically defined autism subtypes, unexpected clinical associations, and rationale for moving forward with this genotype first approach.