Inborn errors of the mitochondrial beta-oxidation of long-chain fatty acids represent an evolving field of inherited metabolic disease. Fatty acid oxidation defects demonstrate an abnormal response to the process of fasting adaptation and affect those tissues that utilize fatty acids as an energy source. These tissues include cardiac and skeletal muscle and liver. Muscle directly uses fatty acids as an energy source whilst hepatic metabolism of fatty acids is mostly directed toward the synthesis of ketone bodies for energy utilization by tissues such as brain. The clinical phenotypes of fatty acid oxidation disorders include disease of one or more of these fatty acid-metabolizing tissues. In this review, we provide an overview of the pathway, discuss the disorders that are well established, and describe recent advances in the field. Currently available diagnostic procedures are critically evaluated.