Despite its well-defined causality, we still don’t know precisely how the polymorphic expansion of the CAG repeat in the first exon of the huntingtin gene results in the pleiotropic, devastating, and ultimately fatal pathophysiology of Huntington’s disease. One long-standing theory posits that the mutated protein adversely affects the cellular machinery that maintains energetic homeostasis and in so doing results in a variety of untoward downstream consequences. A large number of studies have yielded mixed results, with some supporting the ‘energetic hypothesis’ while others have not found convincing evidence for this mechanism. Two large interventional clinical trials of compounds involved in energy production (2 CARE for CoQ10 and CREST for creatine) both failed to meet their efficacy endpoints and provided no additional insights for the selection or design of subsequent energetic drug candidates. Unlike well-defined mitochondriopathies, the purported energetic changes in HD are likely to be subtle, chronic, and progressive. As such, experimental medicine studies in humans that use sensitive and specific measurements need to be conducted to build a highly detailed molecular understanding of any energetics-related deficits in HD-affected individuals. These studies will be critical to refine our mechanistic hypothesis and rationally select targets for pharmacological intervention, design shorter informative trials, and increase the confidence that future drug candidates will benefit patients. Existing data and plans for prospective studies consistent with this strategy will be presented.