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The spleen is a lymphatic organ interposed in the blood stream. It remains a largely neglected aggregate of lymphoid tissue. The spleen immune system is responsible for protecting the body from invading pathogens and detecting senescent, mechanically damaged, displaced and aberrant cells that could lead to tumor formation. Recent studies prove its dominant role in a simultaneous dual reaction to bacterial and allogeneic antigens. Spleen is the site of innate and adaptive immune processes. Microbial penetration of tissues evokes an immediate reaction of the innate system, whereas the adaptive immune response involves the interaction of cells that recognize a particular antigen in context with MHC molecules presented by antigen-presenting cells. This review gives some insight into the immune events in the spleen and its neglected systemic role in the allogeneic reaction.