Strict adherence to medication regimens is generally required to obtain optimal response to combination antiretroviral therapy (ART). Yet, we have made limited progress in developing strategies to decrease the prevalence of nonadherence. As we work to understand adherence in developed countries, the introduction of ART in resource-poor settings raises novel challenges. Qualitative research is a scientific approach that uses methods such as observation, interviews, and verbal interactions to gather rich in-depth information about how something is experienced. It seeks to understand the beliefs, values, and processes underlying behavioral patterns. Qualitative methods provide powerful tools for understanding adherence. Culture-specific influences, medication beliefs, access, stigma, reasons for nonadherence, patterns of medication taking, and intervention fidelity and measurement development are areas ripe for qualitative inquiry. A disregard for the social and cultural context of adherence or the imposition of adherence models inconsistent with local values and practices is likely to produce irrelevant or ineffective interventions. Qualitative methods remain underused in adherence research. We review appropriate qualitative methods for and provide an overview of the qualitative research on ART nonadherence. We discuss the rationales for using qualitative methods, present 2 case examples illustrating their use, and discuss possible institutional barriers to their acceptance