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This chapter provides an approach to the evaluation of lymphadenopathy in children. Malignant etiologies, including HIV-associated malignancies are reviewed. In discussing infectious agents or causes of lymphadenopathy, particular emphasis is placed on chronic regional lymphadenopathy with a focus on new advances in cat-scratch disease and tuberculous and non-tuberculous mycobacterial lymphadenitis. After a suggested preliminary set of laboratory tests, biopsy is often necessary both for histologic and cultural investigation. Therapy must be specific and must follow an accurate diagnosis.