Researchers and clinicians have used numerous methods in their attempts to adequately assess patient compliance (adherence) with medication regimens and to identify noncompliant patients. Large variations have been reported in the extent of noncompliance in individual patients and large populations. In addition, nonadherence has often been poorly defined. Direct measures of adherence include drug assays of blood or urine, use of drug markers with the target medication, and direct observation of the patient receiving the medication. Indirect measures of adherence imply that the medication has been used by the patient; these measures include various forms of self-reporting by the patient, medication measurement (pill count), use of electronic monitoring devices, and review of prescription records and claims. Compliance measures should be assessed on the basis of their validity (sensitivity and specificity or statistical correlation) and the reference standard used. Many early studies used pill counts as a reference standard, but electronic monitoring devices such as the Medication Event Monitoring System have replaced pill counts as the reference standard. The choice of a method for measuring adherence to a medication regimen should be based on the usefulness and reliability of the method in light of the researcher's or clinician's goals. Specific methods may be more applicable to certain situations, depending on the type of adherence being assessed, the precision required, and the intended application of the results.