The Paul-Bunnell test, now 50 years old, is still of fundamental importance in the diagnosis of infectious mononucleosis, even though various immunologic methods have been developed in clinical practice to identify constituents of the Epstein-Barr virus (EBV). The demonstration of sheep red cell agglutinins in infectious mononucleosis (Paul-Bunnell) was in fact the first observation of the presence of heterophil antibodies in this viral disease which was later shown to evoke a polyclonal antibody response to a wide spectrum of autoantigens as well. The selective tropism of EBV for B lymphocytes and the reactivity of T lymphocytes to these infected B lymphocytes are the pathophysiological elements characteristic of infectious mononucleosis, and are the reason for this massive antibody response.