Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders affecting social communication, language and behavior. The underlying cause(s) in a given individual is often elusive, with the exception of clinically recognizable genetic syndromes with readily available molecular diagnosis, such as fragile X syndrome. Clinical geneticists approach patients with ASDs by ruling out known genetic and genomic syndromes, leaving more than 80% of families without a definitive diagnosis and an uncertain risk of recurrence. Advances in microarray technology and next-generation sequencing are revealing rare variants in genes with important roles in synapse formation, function and maintenance. This review will focus on the clinical approach to ASDs, given the current state of knowledge about their complex genetic architecture.