Manifold challenges exist in developing drugs to treat neurological disorders. Issues such as pharmacokinetics of the potential therapeutic compounds, target access, and pharmacodynamic outcomes are frequently overlooked in preclinical development efforts, as are systems biology effects and toxicokinetics. Moreover, it is crucial to understand what the preclinical animal models are actually informing in terms of alignment with the clinical population on which the potential therapeutics will be tested. Mis-alignment animal models with these clinical cohorts likely explain at least some, if not most of the failed clinical trials in Alzheimer’s disease. An iterative discourse between basic and clinical scientists is required to overcome these issues.