Musculoskeletal symptoms may be the initial presentation of a wide variety of systemic non-rheumatic conditions to include metabolic, endocrine, hematologic, and malignant process. Epidemiological features such as gender, ethnicity and age of onset, arthritis pattern, and associated symptoms along with response or lack thereof to empiric treatments provide clues to formulate a broad differential diagnosis. Identifying the primary disorder is crucial for prognostic and therapeutic purposes. In older patients, seronegative patients, or patients whose constitutional symptoms are out of proportion to underlying arthritis, evaluation for underlying malignancy is warranted. Early-onset arthritis may be seen in rare genetic disorders like Wilson’s disease or alkaptonuria. Rheumatologic manifestations are common in sarcoidosis but are frequently misdiagnosed or overlooked. Early osteoporosis and osteoarthritis should raise suspicion for systemic conditions. Amyloid deposition can indolently cause musculoskeletal symptoms mimicking classic primary rheumatic diseases.