Academic medical centers (AMCs) face a weighty regulatory compliance risk in billing Medicare and other third-party payors for clinical trial services. The culture and structure of many AMCs present significant challenges when attempting to coordinate the necessary information and operations to determine whether clinical trial services can be billed to payors or should be charged to an internal research account that tracks the sponsorship monies or grant award. The federal rules are complex, but at base they revolve around the principle that payors should not be billed for clinical trial services that are either being paid by someone else or not provided for the direct clinical care of the patient. With proper coordination and leadership, an AMC can coordinate its efforts, transform its decentralized culture, and achieve a compliance confidence level. Beginning in 2003, the authors helped guide Rush University Medical Center through its landmark voluntary disclosure and settlement with the United States on cancer clinical trial billing. The corrective actions adopted by Rush have set a model that can be adapted for other AMCs. The attention to Medicare’s clinical trials coverage rules brought about by the Rush settlement has led to the Medicare program revisiting its rules and proposing a number of changes that help clarify Medicare policy.