Pharmacological therapy has had limited success in the treatment of most major neurological diseases. This has motivated the development of a number of novel surgical approaches designed to ameliorate drug-induced side effects or pharmacoresistant symptoms. Deep brain stimulation (DBS) has been quite successful in controlling both the cardinal motor manifestation of Parkinson’s disease and the side effects of prolonged levodopa therapy. This has encouraged the application of DBS technology to treat a number of other neurodegenerative conditions, including secondary dystonia associated with pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden–Spatz syndrome), chorea associated with Huntington’s disease, and most recently, cognitive decline associated with Alzheimer’s type dementia. We review the rationale, indications and outcomes of neuromodulation for selected neurodegenerative conditions. In addition to DBS, we discuss select small molecule and gene-based neuromodulatory approaches. Ongoing study of basic pathophysiological mechanisms may eventually allow directed primary prevention of some of these diseases, but until then, invasive neuromoduation will likely continue to play an ever-increasing role in the delivery of the most advanced care for patients with these debilitating conditions.