Removal of the spleen had already been established as a routine technique to treat splenic trauma and other diseases affecting the spleen before the anatomy, physiology, and function of the spleen were known in the mid-twentieth century. It is now widely accepted that the splenectomized individual is at increased risk for infection, in particular, overwhelming post-splenectomy infection (OPSI). OPSI is a syndrome of fulminant sepsis occurring in splenectomized (asplenic) or hyposplenic individuals that is associated with high mortality and morbidity. Poorly opsonized bacteria such as encapsulated bacteria, in particular, Streptococcus pneumoniae, are often implicated in sepsis. The spleen is a reticuloendothelial organ that facilitates opsonization and phagocytosis of pathogens, in addition to cellular maintenance. Splenectomy is associated with an impairment in immunoglobulin production, antibody-mediated clearance, and phagocytosis, leading to an increased risk of infection and sepsis. Early identification of the at-risk patient, early blood cultures prior to antibiotic administration, urgent blood smears and fast pathogen-detection tests, and sepsis bundles should be utilized in these patients. Prompt management and aggressive treatment can alter the course of disease in the at-risk splenectomized patient. Overwhelming postsplenectomy infection can be prevented through vaccination, chemoprophylaxis, and patient education. This article evaluates post-splenectomy sepsis by summarizing the anatomy and function of the spleen, physiological changes after splenectomy that predispose the splenectomized patient to infection, and current management and prevention strategies.