Huntington disease (HD) is an autosomal dominant neurodegenerative disease with complete penetrance. Although the understanding of the cellular mechanisms that drive neurodegeneration in HD and account for the characteristic pattern of neuronal vulnerability is incomplete, defects in energy metabolism, particularly mitochondrial function, represent a common thread in studies of HD pathogenesis in humans and animal models. Here we review the clinical, biochemical, and molecular evidence of an energy deficit in HD and discuss the mechanisms underlying mitochondrial and related alterations.