Although it is well established that axonal transport defects are part of the initiation or progression of some neurodegenerative diseases, the precise role of these defects in disease development is poorly understood. Thus, in this article, rather than enumerate the already well-reviewed evidence that there are transport deficits in disease, I will focus on a discussion of two crucial and unanswered questions about the possible role of axonal transport defects in HD and AD. (1) Are alterations in axonal transport caused by changes in the normal function of proteins mutated or altered in HD and AD and/or do such alterations in transport occur as a result of the formation of toxic aggregates of peptides or proteins? (2) Do alterations in axonal transport contribute to the causes of HD and AD or are they early, or late, secondary consequences of other cellular defects caused by disease-induction?