To date, no candidate intervention has demonstrated a disease-modifying effect in Huntington's disease, despite promising results in preclinical studies. In this commentary we discuss disease-modifying therapies that have been trialled in Huntington's disease and speculate that these failures may be attributed, in part, to the assumption that a single drug selectively targeting one aspect of disease pathology will be universally effective, regardless of disease stage or "subtype". We therefore propose an alternative approach for effective disease-modification that uses 1) a combination approach rather than monotherapy, and 2) targets the disease process early on - before it is clinically manifest. Finally, we will consider whether this change in approach that we propose will be relevant in the future given the recent shift to targeting more proximal disease processes-e.g., huntingtin gene expression; a timely question given Roche's recent decision to take on the clinical development of a promising new drug candidate in Huntington's disease, IONIS-HTTRx.