Clinical exome sequencing has clearly improved our ability as clinicians to identify the cause of a wide variety of disorders. Prior to exome sequencing, a majority of patients with apparent syndromes never received a specific molecular genetic diagnosis despite extensive diagnostic odysseys. Even for those receiving an answer to the question of what caused their disorder, the diagnostic odyssey often spanned years to decades. Determining the particular genetic cause in an individual patient can be challenging due to inherent phenotypic and genetic heterogeneity of disease, technical limitations of testing or both. Blended phenotypes, due to multiple monogenic disorders in the same patient, are true dilemmas for traditional genetic evaluations, but are increasingly being diagnosed through clinical exome sequencing. New sequencing technologies have increased the proportion of patients receiving molecular diagnoses, while significantly shortening the time scale, providing multiple benefits for the health-care team, patient and family.