Infusion of autologous bone marrow-derived mononuclear cells (MNCs) is a promising investigational therapeutic approach for patients with acute ischemic stroke. Preclinical models indicate that MNCs can reduce neurological deficits and enhance recovery. We recently concluded a phase I clinical trial to determine the safety and feasibility of these cells in patients with acute ischemic stroke. In this article, we discuss practical barriers and challenges encountered during the trial and provide lessons learned for the design and planning of future clinical trials testing novel cell therapies for acute ischemic stroke.