Fine-needle aspiration (FNA) biopsy has proven to be a rapid, cost-effective, and accurate means for evaluating a wide variety of conditions in almost any organ system. In some situations, conditions resulting in reactive lymphadenopathies can be discerned on clinical grounds, and many require no specific therapy. However, cases in which an atypical presentation or a prolonged clinical course occurs warrant further investigation of the enlarged lymph nodes, often with the aim of ruling out a malignancy. In such cases, FNA biopsy can provide a rapid and accurate means of ruling out lymphoma and metastatic disease. With the aid of flow cytometry, reactive lymphoid hyperplasia can be readily assessed. Discerning the exact cause of a reactive lymphadenopathy by FNA biopsy can be problematic but can be aided with an appropriate serologic workup (ie, toxoplasma titers, Epstein-Barr virus titers). Granulomatous lymphadenitis may be caused by mycobacterial or fungal organisms, which can be grown in culture or detected by modern molecular studies performed on the aspirated material (ie, PCR). Rapid and accurate assessment of metastatic disease, particularly carcinomas and melanomas, is readily accomplished by FNA biopsy, with an overall sensitivity, specificity, and accuracy of over 90%. In these cases, cell block material can be obtained for additional useful prognostic information.