Christine Eng and colleagues report clinical whole-exome sequencing of 250 individuals representing the first patients referred to the CLIA-certified laboratories at the Baylor College of Medicine for diagnostic exome sequencing (N. Engl. J. Med. doi:10.1056/NEJMoa1306555, 6 October 2013). All patients were referred on the basis of having an undefined genetic condition. The majority of patients were under the age of 18 years, and ∼80% were children with neurological phenotypes. Sequencing was performed with either the Illumina Genome Analyzer IIx platform or the Illumina HiSeq 2000 platform, with mean sequence coverage of over 130β. Variants were classified as deleterious, of unknown clinical significance or benign on the basis of guidelines from the American College of Medical Genetics and Genomics (ACMG). After filtering, the authors identified approximately 400 to 700 potentially clinically useful variants per patient. Variants were confirmed with Sanger sequencing in each proband as well as in parental samples, when available. The authors determined the molecular diagnosis for 62 of the patients (25%), including for 33 individuals with autosomal dominant disease, 6 individuals with autosomal recessive disease and 9 individuals with X-linked disorders. For 30 of the patients, the authors also identified medically actionable incidental findings in 16 genes, 9 of which are recommended for reporting by the ACMG.