Statins are cholesterol-lowering agents which belong to the group of the most commonly prescribed drugs. The use of statins has become the standard treatment in patients with an increased risk of cardiovascular and coronary heart diseases. However, many clinical studies have shown that 13 - 75% of patients fail to achieve LDL-cholesterol and total cholesterol target levels. The clinical implications of insufficient response include cardiovascular complications caused by atherosclerosis leading to acute myocardial infarction, stroke and death. The mechanism underlying statin resistance has been associated with genetic polymorphisms and nongenetic factors (e.g. concomitant diseases, drug-drug interactions, interactions with food and dietary supplements). The article provides a comprehensive update of the current knowledge regarding the role of genetic polymorphism and non-genetic determinants of cholesterol-lowering effect of statins. Dietary aspects of statin efficacy were also presented. The Pubmed search was performed to identify relevant papers from the last ten years which were included in the review. Consideration of the genetic and non-genetic determinants of pharmacological action of statins as well as mechanisms of drug-drug interactions may be useful in clinical practice for improving safety and efficacy of statin treatment.