There are several malaria vaccine candidates at various stages of development. Many of these target blood stages of Plasmodium falciparum. The spleen is a key site for removal of parasitized red blood cells, generation of immunity and production of new red blood cells during malaria. This article describes how all of these processes are modified following infection, and suggests that until we fully understand how these processes function and are modulated by infection, appropriate malaria vaccine design and delivery will be extremely difficult to achieve.