The article addresses several important issues in the measurement of medical resource utilization or direct medical costs when incorporating such measurements into clinical trials. One of the most important issues faced by the analyst relates to the high internal validity of randomized, controlled trials, which require protocol-driven experiences that may falsely increase or decrease costs. The technique of modeling, which will require judgments on the level of detail to include in clinical pathways, can be employed in the identification of costs. Other important issues include attribution of costs to disease or treatment and assignment of monetary values. Sources of cost data, reimbursement coding systems, and resource valuation data sources in the United States are described. Finally, the trade-offs inherent in including economic evaluations in Phase III clinical trials are addressed and specific guidelines for performing economic evaluations in clinical trials are provided.