From a pathologic-anatomic perspective, the splenic parenchyma is divided into red and white pulp, which react to a certain extent independently from one another in the context of systemic and local processes. While the red pulp serves to filter blood, the white pulp, together with the perifollicular marginal zone, organizes immune reactions. In the marginal zone, innate and acquired immune responses are integrated. The vast majority of splenectomies serve therapeutic purposes in the context of already known disease. Therefore, only about 10% of splenectomy specimens are diagnostic challenges, including the diagnosis of haematological diseases, splenomegaly or splenic tumors. Differential diagnosis considerations are discussed based on the clinical presentation.