Muscle pain is one of the most common, as well as elusive, clinical complaints. Pain can be experienced in muscles by any dysfunction of the muscle itself, peripheral nerves, or central nervous system. Persistent inflammation of the muscle increases nerve endings of the nociceptors and can develop allodynia or hyperalgesia. Myofascial trigger points are formed by perpetuating contraction of the sarcomeres and local ischemia and can result in regional pain. Disorders of the peripheral nervous system can entail muscle pain in the innervated territory. The central nervous system can also modulate or generate muscle pain. Gate-control theory provides an explanation as to how pain can be affected by the nervous system. Fibromyalgia is believed to be related to a lowered pain threshold in the central nervous system. Clinicians, during their diagnostic approach, should not unduly attribute muscle pain to pathology confined to the muscle merely because pain is perceived and evoked from the muscle. Even in cases where abnormalities are confirmed in the muscle, such as myofascial trigger points, clinicians should seek the underlying etiology. In particular, diagnosis of myofascial pain syndrome does not rule out primary musculoskeletal disorders. Rather, arthropathies or radiculopathies are known to frequently involve myofascial pain syndrome, which would not improve unless they are resolved. After accurate diagnosis of muscle pain is obtained, appropriate treatment should be implemented. A multi-disciplinary, individualized approach, including physiotherapy, exercise, education, and behavioral modification, is recommended.