Cell therapy offers the possibility of replacing degenerated neurons thereby improving the symptoms of neurodegenerative disorders such as Huntington's disease. However, clinical benefits in patients with Huntington's disease, if any, have been transient and modest. Grafts survived well at 18 months in one patient with Huntington's disease, but graft survival was markedly attenuated by 10 years in three other patients from this transplantation cohort. It is critical to delineate the causes of graft degeneration if such therapies will be utilized in patients with a goal of achieving meaningful clinical benefit. Similar challenges may also accrue to future stem cell therapies. Here we discuss the potential causes of suboptimal long-term graft survival in patients with Huntington's disease, including allograft immunoreactivity, microglial responses targeted to grafted cells and cell-to-cell neurotoxicity. We also discuss similar challenges and unique differences comparing neuronal grafts in patients with Parkinson's and Huntington's diseases.