Controlled clinical studies and clinical experience over many years have proven that virtually all patients benefit from lipid-lowering therapy with statins, even those with normal LDL cholesterol levels. Several recent large outcome trials have further demonstrated the clinical benefits and safety of statins in patients with a wide-range of high risks for cardiovascular disease. Those patients at highest absolute cardiovascular risk generally have the most to gain from statin therapy. A variety of statins are available to lower plasma lipids to guideline levels, but all differ in their pharmacokinetic properties, drug interaction profiles, and risk of myotoxicity. This has been highlighted by the withdrawal of cerivastatin from the market as a result of serious safety concerns. This review examines the safety and effectiveness of statins in special populations at high risk of cardiovascular disease—patients with coronary heart disease, dyslipidaemia, diabetes, hypertension, nephrotic disease, HIV, organ transplant patients and the elderly—with a focus on clinically relevant differences in the properties of individual statins that may influence the risk of drug interactions and side effects.