Although neurodegenerative diseases exhibit distinct pathologies, such as affected neuronal cell population, age of onset, and pathological symptoms, overlapping characteristics can be observed at the cellular level. In particular, several neurodegenerative diseases display defects in intracellular vesicular trafficking. Here we discuss the range of cellular phenotypes observed in two rare neurodegenerative diseases, Niemann-Pick Type C and Huntington's Disease, both of which involve vesicular trafficking defects that may contribute to neuronal cell death. In NPC, the primary defect is cholesterol and glycosphingolipid accumulation, but NPC mutant cells display widespread trafficking alterations. In HD, protein aggregates are a hallmark feature, but HD cells also exhibit changes in vesicular traffic, including axonal transport and early endosomal trafficking, that likely impact neuronal cell viability. Here we discuss current therapies that seek to address cellular defects in NPC and HD and describe areas of investigation that may lead to new therapeutic treatment.