This study reports on the initial clinical indications for clinical exome sequencing (CES) referrals and molecular diagnostic rates for different indications and test types. The study involved 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. CES was performed as trio-CES (sequencing both parents and their affected child simultaneously) or proband-CES (sequencing only the affected individual). The overall molecular diagnosis rate was 26% (213 out of 814 cases). The molecular diagnosis rate for trio-CES was 31% (127 out of 410 cases), while it was 22% (74 out of 338 cases) for proband-CES. In cases of developmental delay in children (55 years, n = 138), the molecular diagnosis rate was 41% (45 out of 109 cases) for trio-CES and 9% (2 out of 23 cases) for proband-CES. The significantly higher diagnostic yield for trio-CES was due to the identification of de novo and compound heterozygous variants. The study concludes that trio-CES is associated with a higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods, particularly for genetically heterogeneous conditions such as developmental delay.This study reports on the initial clinical indications for clinical exome sequencing (CES) referrals and molecular diagnostic rates for different indications and test types. The study involved 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. CES was performed as trio-CES (sequencing both parents and their affected child simultaneously) or proband-CES (sequencing only the affected individual). The overall molecular diagnosis rate was 26% (213 out of 814 cases). The molecular diagnosis rate for trio-CES was 31% (127 out of 410 cases), while it was 22% (74 out of 338 cases) for proband-CES. In cases of developmental delay in children (55 years, n = 138), the molecular diagnosis rate was 41% (45 out of 109 cases) for trio-CES and 9% (2 out of 23 cases) for proband-CES. The significantly higher diagnostic yield for trio-CES was due to the identification of de novo and compound heterozygous variants. The study concludes that trio-CES is associated with a higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods, particularly for genetically heterogeneous conditions such as developmental delay.