Over the past three decades, statins have become the cornerstone of prevention and treatment of atherosclerotic cardiovascular and metabolic diseases. Albeit generally well tolerated, these drugs can elicit a variety of muscle-associated symptoms that represent the most important reason for treatment discontinuation. Statin-associated myopathy has been systematically underestimated by randomized controlled trials as compared with the incidence observed in clinical practice and obtained from patient registries. There are several reasons for this discrepancy, among which the lack of reliable diagnostic tests and a validated questionnaire to assess muscle symptoms are recognized as unmet needs. Here, we review the cellular and molecular mechanisms underlying statin-associated myopathy and discuss the experimental and clinical data on various biomarkers to diagnose and predict muscle-related complaints.