Interleukin-2 (IL-2) is an effective activator of lymphocytes with anti-neoplastic properties such as T-cells or natural killer cells, and this property of IL-2 has formed the basis for its widespread used as an immunotherapeutic agent in human neoplastic disease. In recent years, IL-2 therapy for solid neoplastic diseases and hematopoietic cancers has been supplemented with histamine dihydrochloride with the aim of counteracting immunosuppressive signals from monocytes/macrophages. Here we review the preclinical basis for the use of histamine as an adjunct to IL-2 in cancer immunotherapy.