Since ancient times, the spleen is regarded as a mysterious and intriguing organ. It has various functions underscoring its prepoderant relevance as the largest secondary lymphoid organ system. Total splenectomy done at any age and for any reason increases the risk of death from overwhelming postsplenectomy infection (OPSI). The etiologic agents most frequently found in OPSI are Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitidis, but other bacteria such β-hemolytic Streptococcus, Staphylococcus aureus, and Escherichia coli, Pseudomonas sp., also present a significant risk. Prophylaxis of OPSI is located in three main categories: patient education, immunoprophylaxis, and chemoprophylaxis. Besides these, the realization of heterotopic splenic autotransplantation after splenectomy seems to favor the recovery of some of the functions of the spleen. However, these measures seem to be not sufficient to prevent the higher risk of developing OPSI. Because of this risk, the indication for the realization of total splenectomy in trauma and several diseases has been sharply declining. The objective of this work is to make a description of the aspects that correlate the absence of spleen with the occurrence of sepsis.