The spleen is an important lymphoid organ, involved in immune responses against all types of antigen that appear in the circulation. Its complex anatomical organization, with distinct compartments containing specialized cell types, provides a microenvironment which allows different cell-cell interactions and determines the direction of developing immune responses. In this review we evaluate the vast amount of in vitro data dealing with antigen presentation, cell-cell interactions, T and B cell activation, and the immunoregulatory role of cytokines, as suggested to be involved in immune responses. As a basis for understanding of in vivo processes, these in vitro data will be related to discrete phenomena of in vivo immune responses, such as antigen localization/trapping, cell migration patterns of immunocompetent cells, cytokine production, and antibody formation in the different compartments of the spleen. Finally, we try to bring order to the sequence of events that occur in the spleen after antigenic challenge by presenting an in vivo model for T cell dependent and T cell independent immune responses.