Evidence-based evaluations of clinical preventive services help define priorities for research in prevention as part of primary health care. In this article, we draw on our experiences with the U.S. Preventive Services Task Force (USPSTF) to outline some major areas where research is needed to define the appropriate use of specific screening tests, counseling interventions, immunizations, and chemoprophylaxis. Areas of particular importance included research to: (1) Identify effective and practical primary care interventions for modifying personal health practices of patients, especially around issues such as diet, exercise, alcohol and drug use, and risky sexual behavior; (2) Clarify the optimal periodicity for certain screening tests and counseling interventions; (3) Identify practical ways to allow patients to share decision-making about preventive care, especially for services of possible but uncertain benefit; (4) Examine the most sensitive and efficient ways to identify high-risk groups who may need different services than the average population; and (5) Expand the use of decision-analysis and cost-effectiveness analysis to help identify optimal use of clinical preventive services. Given the difficulty of large, prospective trials, we discuss the use of alternative research designs to fill in critical gaps in the evidence for the effectiveness of specific services. Finally, we note several issues of increasing importance that may need to be addressed by future work of the USPSTF: what are the most reliable and effective ways to (1) measure and (2) improve the delivery and quality of preventive care provided in the primary care setting.