Epstein-Barr virus (EBV) is the cause of infectious mononucleosis and is associated with severe infections in immunocompromised patients. EBV is also causally linked with several human malignancies. The heterophile antibody test and EBV-specific antibody tests remain the principal means of diagnosis of initial infection in otherwise healthy patients. Enzyme-linked immunosorbent assays have replaced the traditional immunofluorescence assays for EBV-specific antibodies. Several newer molecular diagnostic tests have become available that facilitate accurate monitoring of infection. The role of these tests for patients with uncomplicated infectious mononucleosis is limited, although these tests are being increasingly used to monitor the state and level of EBV replication for severe infections and among immunocompromised patients. Antiviral therapy has a limited, short-term effect on oropharyngeal shedding but has proven ineffective for the clinical manifestations of infectious mononucleosis. Patients with selected complications frequently benefit from short-term corticosteroid therapy.