The complexity of the immune system presents a formidable challenge to the identification of therapeutic targets. Experience from knockout mice tells us that targeting a single molecule will often have no effect, owing to redundancy in the immune system, or that, conversely, it can reveal unexpected and undesirable systemic effects. However, there is hope that some molecular targets might be therapeutically useful. On page 106, Amanda Proudfoot argues that chemokine receptors are valid targets for therapy despite the seeming redundancy within the chemokine–chemokine-receptor system. Also, on page 116, Arlene Sharpe and Gordon Freeman provide an update on the expanding family of B7 co-stimulatory molecules and their specific roles in immunity and disease, with comment on how they might be targeted in new immunotherapies. Cytokines are another crucial component of immune regulation, and a highlight article on page 73 — Inflammation blockade — discusses a recent report identifying the cytokine signal regulator SOCS3 as a potential target in rheumatoid arthritis.

Of course, targeting regulatory molecules can be a blunt tool: both harmful and beneficial immune responses are affected. It will therefore be important to develop antigen-specific immunotherapies that block only the harmful immune response, leaving normal immune function intact. One hurdle to this antigen-specific approach is the diversification of epitope specificity that occurs during inflammatory immune responses owing to the release and presentation of new antigenic epitopes — a phenomenon known as epitope spreading. On page 85, Steve Miller and Carol Vanderlugt discuss new data on the role of epitope spreading in autoimmune disease and transplant rejection, and their implications for antigen-specific immunotherapy.