In a climate of increased expectation for the translation of research, academic clinical research units are looking at new ways to streamline their operation and maintain effective translational support services. Clinical research, although undeniably expensive, is an essential step in the translation of any medical breakthrough, and as a result, many academic clinical research units are actively looking to expand their clinical services despite financial pressures. We examine some of the hybrid academic-business models in 19 clinical research centers within the Clinical and Translational Science Award consortium that are emerging to address the issue of cost recovery of clinical research that is supported by the United States federal government. We identify initiatives that have succeeded or failed, essential supporting and regulatory components, and lessons learned from experience to design an optimal cost recovery model and a timeline for its implementation.