Lymph node enlargement is a common problem in children and adolescents. As part of the reticuloendothelial system, lymph nodes serve as the termination point for lymphatic vessels that drain lymph from most tissues of the body. Nodes are densely packed with lymphocytes that are organized loosely into cortical nodules and medullary cords by connective tissue, trabeculae, and lymphatic sinuses. The juxtaposition of the phagocytic cells, antigen presenting cells, and lymphocytes in areas of sluggish blood flow is ideally suited to provide the first line of defense against pathogens. Lymph node enlargement may result from acute or chronic, infectious or noninfectious stimuli. Organizing the possible causes of lymphadenopathy by anatomic location and origin aids the clinician in the evaluation.