Acute ischemic stroke is a leading application of intra-arterial stem cell delivery, and it reveals the unique challenges of stem cell therapy for neurological diseases. Effective arterial delivery of stem cell therapy is a complex process that requires proper selection and preparation of immune-compatible stem cells, injection of optimal doses of cells at an opportune time that ensures maximum survival, and methods to track their delivery and deposition. The challenges in effective arterial delivery are significant, starting with patient selection, the type and source of the stem cells, preparation and optimization for specific applications, safe dosing, monitoring delivery and uptake of cells during injection, and assessing response afterward. This chapter reviews the sources, processing, applications, and limitations, as well as the potential of arterial stem cell delivery.