Mitochondrial respiratory chain disorders (RCDs) collectively represent the most common inborn errors of metabolism. They are defined by a biochemical defect in the electron transport chain and can impact one or more organ systems, in infancy or in adulthood.  Their diagnosis and management are incredibly challenging, with no proven therapies to date.  Our laboratory has developed “integrative genomics” strategies to discover genes underlying these disorders, in which we combine the power of human genetics with integrative strategies to prioritize and pinpoint causal genes.  Using this approach, we and our collaborators have discovered over 20 Mendelian disease genes.  We are currently applying next-generation genomics and metabolomics methods to understand how these mutations lead to end organ pathology — not only do these studies provide insights into mechanism, they also yield quantitative biomarkers with which to track disease severity.