In the treatment of central nervous system diseases, therapeutic particles need to breach the blood–brain barrier (BBB) to reach their intended target, and it has long been known that this is a difficult barrier to breach. The barrier is both passive with tight junctions hindering passage of even rather small molecules, as well as active with transporters that can pump select molecules back into the bloodstream. The diseases include both those where this barrier has been compromised such as brain tumors, hemorrhagic stroke, and neurotrauma; as well as neurodegenerative disorders where the compromise is substantially less and often unnoticeable. In addition to the pharmaceutical solution which involves design of small molecules that may be administered orally or at least systemically, there is also a compelling need at present to design devices for direct delivery of therapeutics into the central nervous system. Such delivery methods are unpopular because of their intrusiveness; however, the lack of success of the systemic route in the treatment of many of the most severe brain diseases has established a need for such devices, and the success and popularity of deep brain stimulation (DBS) has lowered the psychological barrier to these. Many clinical trials are under way which demand direct delivery of therapeutics to the brain. Such therapeutics range from small molecules, large proteins, nanoparticles, and viral carriers for gene therapies, to cells. This chapter is a review of intraparenchymal delivery of such therapies for brain diseases and of the devices used for such purposes.