Physical inactivity is increasing in virtually all developed and developing countries and is estimated to cause 2 million deaths worldwide annually. Conversely, regular exercise contributes to the primary and secondary prevention of cardiovascular disease, improves wellness, attenuates age-related decline and reduces risk of premature death. However, it is widely believed that lifestyle interventions are difficult to institute and difficult to maintain and drugs, particularly statins, should be considered as the fundamental tool in the prevention of coronary artery disease. It is therefore a concern that statins may adversely affect the muscle's ability to appropriately respond to physical exertion. Statin therapy can induce skeletal muscle damage in treated patients, despite their being asymptomatic and without increment of serum creatine kinase level. In clinical practice, muscle complaints due to statin therapy are easily dismissed by the patient and physician. Such muscle effects are likely related to mitochondrial dysfunction and may well affect 25% of statin users who exercise and thus constitute one of the most common and underappreciated side effects of statins. Physical activity is affordable to all, as opposed to statins, and should be regarded as one of the most cost-effective ways to prevent cardiovascular disease. Physicians should be aware that statins may interfere with patient's activity levels.