Maple syrup urine disease results from defective function of the branched chain alpha-ketoacid dehydrogenase complex [BCKD] within the matrix of the mitochondria. This disorder in humans is inherited as an autosomal recessive trait with an incidence of 1 in 150,000 live-births in the general population and 1/176 for the Mennonite population. Over 50 different causal mutations are known to exist scattered among the three genes unique to the catalytic function of the enzyme complex. The defect was first described in 1954 and much has been learned about the genes and proteins involved in this rare human disorder. The enzyme is present in all mammalian cells that contain mitochondria, and the activity of BCKD is regulated by phosphorylation through a complex-specific kinase. Expression of the kinase is regulated by metabolic and hormonal components. Naturally occurring mutations are used to define the molecular mechanisms of transcription, translation, protein import into mitochondria and the assembly of the component proteins into a functional complex. The long-term pathophysiology of BCKD dysfunction remains to be explained. What began as a focused interest in BCKD due to the associated disease, has broadened into a quest to understand the role of BCKD in regulation of leucine levels and in turn controlling protein metabolism and hormone release.