Infectious mononucleosis is a clinical entity characterized by a sore throat, cervical lymph node enlargement, fatigue, and fever most often seen in adolescents and young adults. Infectious mononucleosis is most often caused by a primary Epstein-Barr virus (EBV) infection. EBV is a γ-herpesvirus that infects at least 90% of the population worldwide. The virus is spread by intimate oral contact among teenagers and young adults. How preadolescents acquire the virus is not known. A typical clinical presentation with a positive heterophile antibody test is usually sufficient to make the diagnosis, but heterophile antibodies are not specific and do not develop in some patients, especially preadolescent children. EBV-specific antibody profiles are the best choice for confirming and staging EBV infection. Besides causing acute illness during primary infection, there can also be long-term consequences from acquiring this virus, such as certain cancers and autoimmune diseases, as well as complications of primary immunodeficiency in persons with certain genetic mutations. Future challenges are to develop prophylactic and therapeutic vaccines and effective specific treatment strategies.