Over the past two decades it has become clear that the ability of a host to generate antibodies against a wide variety of potential antigens is due to structural diversity in the antibody molecule within the variable region. This diversity results in sites within the molecule that are themselves immunogenic. These immunogenic sites are called idiotopes, and the collection of idiotopes on a single antibody molecule determines that antibody's idiotype. The idiotype of an antibody molecule is defined serologically by a second antibody termed an anti-idiotype. Anti-idiotypic antibodies can recognize antibody molecules bearing similar or identical structures within the variable regions, which are often on or near sites of antigen binding. Investigation into the nature of idiotype and anti-idiotype interactions has increased our knowledge of antibody structure, antigen-antibody interactions, the regulation of antibody production, and the nature of autoimmune disorders. This review will discuss the nature of idiotypes and anti-idiotypes and their potential role in the diagnosis, management, and treatment of autoimmune, infectious, and malignant diseases.