Recent years have seen dramatic advances in our understanding of the genetic architecture of autism. Studies driven by genotyping technology, such as the Autism Genome Project's (AGP) phase 1 and phase 2 efforts, have led to an appreciation of risk conferred by sequence as well as structural variants, and the perturbation of biological pathways they represent. However, it is increasingly clear that the limited resolution of genotyping technology will minimize the potential for additional high impact discovery going forward, and that the rapidly declining cost of sequencing makes exome and whole genome sequencing, in spite of methodological and analytical challenges, the logical next steps for achieving a more comprehensive understanding of the genetic risk factors for autism. Indeed, several NIH ARRA grants were awarded to teams exploring exome sequencing, including members of the AGP. This project will explore methodological and analytical approaches to exome and whole genome sequencing, and position the AGP for the next phase in autism genetics research, large scale whole genome sequencing. The AGP aims to 1) conduct genotyping experiment on 3,000 ASD samples using exome chip built to capture all exome variants observed at least twice in a large samples of exomes (N>10,000), and 2) perform whole genome sequencing on 75 samples where microarray or exome sequencing had failed to identify all etiologic variants. The project will also generate a tremendous amount of data available to the entire AGP community; thereby revitalizing the Consortium and preparing it to lead in the era of applying whole genome sequencing to study ASD. The ultimate goal is to further delineate all of the genetic factors involved in ASD, having a transformative impact on the AGP, and more importantly on the entire autism field.