Cell therapy offers the possibility of replacing degenerated neurons thereby improving the symptoms of neurodegenerative diseases such as Huntington’s disease (HD). However, clinical benefits in patients with HD, if any, have been transient and modest. Grafts have been demonstrated to survive well at 18 months in one patient with HD, but graft survival was markedly attenuated by 10 years in two 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. I will discuss the potential causes of suboptimal long-term graft survival in HD patients, which we suggest include allograft immunoreactivity, microglial responses targeted to grafted cells and cell-to-cell neurotoxicity.