Extraordinary advances in understanding of the molecular bases of neurodegeneration have occurred since the Huntington's disease genetic mutation was discovered. Many relevant routes to neuronal demise in Huntington's disease have been identified including: glutamatergic stress, metabolic insufficiency, oxidative stress, proapoptotic signaling, inflammatory signaling, altered proteolysis, protein aggregation, transcriptional dysregulation, abnormal protein folding and neurotrophin insufficiency. Each represents specific therapeutic opportunities, which are being tested in high-throughput screens as well as in genetic models of Huntington's disease, transgenic mouse models and human clinical trials. Challenges include the uncertain power of these preclinical studies to predict therapeutic efficacy in humans, prioritizing the many approaches for human clinical trials and learning how to perform neuroprotective trials in presymptomatic individuals while protecting them from unwanted genetic information.