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Background: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular disease, the leading cause of death worldwide. In the last twenty years, effective lipid-lowering therapies, particularly statins, have become widely available to prevent and reverse the progression of disease. However, there is a significant gap between expected and actual benefits; this may be attributed to poor adherence to statin therapy. Objective: To define the extent, causes (including psychological aspects), consequences and management of non-adherence to statins. Methods: Literature using PubMed and Medline up to and including 30 July 2009. Results: Adherence to statin therapy is suboptimal in both primary and secondary prevention of cardiovascular disease. Causes vary, and include patient factors (e.g., comorbidities, financial constraints, psychological issues), practitioner factors (e.g., poor knowledge of adherence, time constraints, poor communication skills and patient–doctor working alliance) and system factors (e.g., medication costs, lack of clinical monitoring, drug side effects). Non-adherence is associated with adverse health outcomes and increased costs of healthcare. A framework, based on a multidisciplinary approach, for addressing non-adherence, including managing the statin-intolerant patient, is presented. Conclusions: Non-adherence to statins is a significant issue for the prevention and treatment of cardiovascular disease. Increased awareness of the causes and solutions for overcoming non-adherence, including safer prescribing, improvement in physician–patient alliance and reduction in drug costs, will enhance the cost-effectiveness of the use of statins and significantly improve patient care and outcomes.