Progress in regenerative medicine seems likely to produce new treatments for neurologic conditions that use human cells as therapeutic agents; at least one trial for such an intervention is already under way. The development of cell-based interventions for neurologic conditions (CBI-NCs) will likely include preclinical studies using animals as models for humans with conditions of interest. This paper explores predictive validity challenges and the proper role for animal models in developing CBI-NCs. In spite of limitations, animal models are and will remain an essential tool for gathering data in advance of first-in-human clinical trials. The goal of this paper is to provide a realistic lens for viewing the role of animal models in the context of CBI-NCs and to provide recommendations for moving forward through this challenging terrain.