The spleen contains hematopoietic and lymphoid elements, is a primary site of extramedullary hematopoiesis, and removes degenerate and aged red blood cells as well as particulate materials and circulating bacteria from the blood supply. Lesions of this important component of the immune system may center on the red pulp, the white pulp or involve both compartments The spleen is the site of direct and indirect toxicity, a target for some carcinogens, and also a site for metastatic neoplasia. Many systemic or generalized diseases have splenic involvement. This paper documents spontaneous background and treatment-induced lesions seen in rodent toxicity and carcinogenicity studies.