Prescription medications enhance the well-being of most chronically ill patients. Many individuals, however, struggle with how to pay for their treatments and as a result experience problems with self-care and health maintenance. Although studies have documented that high out-of-pocket costs are associated with medication non-adherence, little research on prescription cost sharing has been theoretically grounded in knowledge of the more general determinants of patients' self-management behaviors and chronic disease outcomes. We present a conceptual framework for understanding the influence of patient, medication, clinician, and health system factors on individuals' responses to medication costs. We review what is known about how these factors influence medication adherence, identify possible strategies through which clinicians, health systems, and policy-makers may assist patients burdened by their medication costs, and highlight areas in need of further research. Although medication costs represent a burden to chronically ill patients worldwide, most patients report using their medication as prescribed despite the costs, and others report cost-related underuse despite an apparent ability to afford those treatments. The cost-adherence relationship is modified by contextual factors, including patients' characteristics (e.g., age, ethnicity, and attitudes toward medications), the type of medications they are using (e.g., the complexity of dosing and the drug's clinical target), clinician factors (e.g., choice of first-line agent and communication about medication costs), and health system factors (e.g., efforts to influence clinicians' prescribing and to help patients apply for financial assistance programs). Understanding these relationships will enable clinicians and policy-makers to better design pharmacy benefits and assist patients in taking their medication as prescribed. The next generation of studies examining the consequences of prescription drug costs should expand our knowledge of the ways in which these co-factors influence patients' responses to medication cost pressures.