Although the long- and short-term safety of statin therapy is well established, statin intolerance is common in clinical practice. Muscle symptoms are the most common side effect of statin therapy and are potentially the most hazardous and the most likely to reduce patient adherence. Clinicians can establish office protocols/procedures that will reduce the number of patients with statin intolerance. Genomic variations that result in statin-associated myopathy are likely. We await diagnostic and treatment options for this group. Alternative dosing options and the use of alternative statins are useful strategies for those with muscle symptoms. Therapeutic lifestyle changes are critical to achieving maximal risk reduction but remain difficult to implement. Presently available nonstatin lipid-lowering drugs (alone or in combination) do not have the established benefit of statins but do have potential benefit in select patients.