This is a descriptive article outlining issues in the development and implementation of a multisite randomized rehabilitation trial for brain injury treatment. The goal of this article is to present practical and theoretical considerations in designing and conducting multicenter rehabilitation trials. Practical issues discussed include (a) treatment setting, (b) patient accessibility in determining the research question of interest, as well as inclusion and exclusion criteria, (c) research protocol development in the context of rehabilitation standard of care, and (d) protocol treatments in the context of realistic cost-benefits analysis. Rehabilitation theory is discussed as playing an important role designing the specifics of the protocol interventions. The Defense and Veterans Brain Injury Center Veterans Health Administration cognitive-didactic versus functional-experiential study methodology is used for illustrative purposes. This study evaluated 2 alternative approaches to treatment: one focusing on underlying cognitive processes and the second on errorless learning in everyday functional situations. Lessons learned over the course of completing the treatment trial are discussed.