CD20 is a 33-37 kDa, non-glycosylated phosphoprotein expressed on the surface of almost all normal and malignant B cells. It is also the target for rituximab, the most effective anti-cancer monoclonal antibody developed to date. Rituximab has now been given to over 300,000 lymphoma patients in the last decade and interestingly is now being explored for use in other disorders, such as autoimmune conditions including rheumatoid arthritis and systemic lupus erythematosus. Despite the success in immunotherapy, knowledge about the biology of CD20 is still relatively scarce, partly because it has no known natural ligand and CD20 knockout mice display an almost normal phenotype. However, interesting insight has come from work showing that CD20 is resident in lipid raft domains of the plasma membrane where it probably functions as a store-operated calcium channel following ligation of the B cell receptor for antigen. In the current review, these and data relating to its activity as a therapeutic target will be discussed in depth. It is clear that a greater understanding of CD20 biology and the effector mechanisms, such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and growth regulation, which operate with anti-CD20 mAb in vivo will allow more efficient exploitation of CD20 as a therapeutic target.