Lymphadenopathy occurs in 0.6% of the population annually, usually from a benign cause. History should focus on lymph node location, duration of lymphadenopathy, associated symptoms (particularly fever, night sweats, and unintentional weight loss), past and current medical conditions, occupation, travel history, animal exposures, medication use, recent vaccine history, drug use, sexual history, and family history. Physical examination should first differentiate localized from generalized lymphadenopathy. Generalized lymphadenopathy is usually caused by underlying systemic disease. Although usually benign, localized lymphadenopathy may represent infection or malignancy, particularly if epitrochlear or supraclavicular nodes are affected. Lymph nodes that are larger than 2 cm, hard, or matted/fused to surrounding structures may indicate malignancy or granulomatous diseases, especially in children. When lymphadenopathy persists beyond four weeks or is accompanied by systemic symptoms, imaging and appropriate laboratory studies (eg, complete blood cell count, C-reactive protein, erythrocyte sedimentation rate, tuberculosis testing) should be obtained. Biopsy may be performed through fine-needle aspiration, core needle biopsy, or excisional biopsy. Antibiotics may be considered if a benign or self-limiting etiology (eg, bacterial lymphadenitis) is suspected. Corticosteroids should be avoided because they can mask the histologic diagnosis of lymphoma or other malignancy.