The conventional approach to developing disease-modifying treatments for neurodegenerative conditions has been to identify drivers of pathology and inhibit such pathways. Here we discuss the possibility that the efficacy of such approaches may be increasingly attenuated as disease progresses. This is based on experiments using mouse models of spinocerebellar ataxia type 1 and Huntington's disease (HD), where expression of the dominantly acting mutations could be switched off, as well as studies in human HD, which suggest that the primary genetic driver of age-of-onset of disease is a much weaker determinant of disease progression in affected individuals. The idea that one may approach a point in the disease course where such rational therapeutic strategies based on targets which determine onset of disease have minimal efficacy, suggests that one needs to consider other approaches to therapies and clinical trial design, including initiation of therapies in presymptomatic individuals.