This chapter focuses on the challenges presented by therapeutic targets in the central nervous system (CNS), the manner in which animal models have and can be used to support the translation of therapeutic biologies to the human CNS, the blood brain barrier (BBB), and the uncertainties of CNS drug exposures. It also addresses how these challenges can be met and the associated risks of CNS therapeutic development mitigated. Animal CNS disease models are unique tools that have led to a significant increase in the number of potential new therapeutic targets and an improved understanding of the biologies underlying disease processes. Development of pharmacodynamic (Pd) biomarkers for CNS drug development should be a high priority. Pd biomarkers are used in Phase 1, 2, and 3 studies, although most commonly in Phase 1 and 2 studies.