The rational use of laboratory testing to investigate early, undifferentiated joint pain depends heavily on a detailed history and careful physical examination. Nevertheless, several diagnostic tests have some discriminatory function in the initial evaluation of soft tissues and joint complaints, given the correct clinical context. Arthrocentesis frequently gives the best results when compared with other tests in the differential diagnosis of monoarticular and polyarticular joint pain. There is also a role for radiographs, and less frequently, magnetic resonance imaging. Although overuse of an arthritis panel is not recommended, for an appropriately chosen patient, complete blood cell count, serum uric acid, C-reactive protein (or erythrocyte sedimentation rate), rheumatoid factor, antiecyclic citrullinated peptide, and antinuclear antibody titers form a reasonable screening panel when rheumatic disease is suspected based on the clinical condition. Other tests might include a purified protein derivative, anti-Borrelia titers, and antibodies for antistreptolysin O. However, many rheumatic conditions can be diagnosed or at least suspected on clinical grounds alone, and a careful history and physical examination are absolutely essential for the appropriate use of any laboratory testing. © 2010.