Differentiating the cause of pain and dysfunction due to cervical spine and shoulder pathology presents a difficult clinical challenge in many patients. Furthermore, the anatomic region reported to be painful may mislead the practitioner. Successfully treating these patients requires a careful and complete history and physical examination with appropriate provocative maneuvers. An evidence-based selection of clinical testing also is essential and should be tailored to the most likely underlying cause. When advanced imaging does not reveal a conclusive source of pathology, electromyography and selective injections have been shown to be useful adjuncts, although the sensitivity, specificity, and risk–reward ratio of each test must be considered. This review provides an evidence-based review of common causes of shoulder and neck pain and guidelines for assistance in determining the pain generator in ambiguous cases.