The mission of the National Heart, Lung, and Blood Institute is to sponsor research in the prevention, diagnosis, and treatment of heart, lung, and blood diseases. As a part of its activities toward this end, the Institute plans and conducts clinical trials that test the safety and efficacy of a broad range of preventive and treatment regimens. Many of these trials involve thousands of patients and require the cooperation of many research clinics under a common protocol, often for many years. An essential component in these efforts is a standardized methodology to allow accurate tracking of adherence patterns so that problem adherence situations can be identified and rectified. This article reviews the methods that have been used to assess adherence patterns in selected clinical trials supported by the NHLBI. The most frequently used methods have been pill count and direct measurement of the drug, its metabolites, or physiological effects in some bodily fluid. Supplementary information is frequently obtained by self-report. Experience with markers has been very limited and no systematic data are available. The Aspirin Myocardial Infarction Study is used as a case study to illustrate specific strengths and weaknesses of three types of adherence assessment methods, namely, assay of salicylates in the urine, platelet aggregation, and pill count. Generalizations to other clinical trials are discussed. Based on experience to date with traditional methods of compliance assessment, several conclusions are drawn. Combinations of measures, in general, provide the most useful profiles of adherence patterns in clinical trials. The development of an ideal marker compound with appropriate safety for long-term administration would be of use to overcome a number of assessment problems, including (1) inability of current methods to determine temporal patterns of drug consumption, (2) need for more precise quantification of consumption levels beyond a simple “drug present or drug absent” result, (3) providing cheaper or more convenient alternatives to direct analyses of the drug or its metabolites, (4) reducing assessment errors due to non-specificity of analytic methods and individual metabolic variations, and (5) as a supplement to pill counts to assess placebo tablet consumption.