De novo mutations are spontaneous mutations that are detected in a child but not in either parent. Two well-powered family-based exome sequencing studies targeting de novo mutations reveal novel insights into the genetic architecture of autism spectrum disorders (ASDs). The first study by Iossifov et al. analysed the genomes of >2,500 'simplex' families — that is, families in which neither parent nor siblings of a child with ASD are affected — and showed that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting mutations contribute to 12% and 9% of diagnoses, respectively. Of note, genes affected by spontaneous mutations were often expressed during embryonic development or encoded chromatin-remodelling proteins. The latter finding was also reported in the second study by De Rubeis et al., who sequenced the exomes of 3,871 autism cases and 9,937 ancestry-matched or parental controls. The researchers also found that mutated genes were enriched for those encoding products involved in synaptic formation and transcriptional regulation. Together, these studies highlight the promising role of exome sequencing for the discovery of disease-relevant genes in neuropsychiatric disease.