The generation and maintenance of immune responses are controlled by both co-stimulatory and co-inhibitory signalling through T cell co-receptors, many of which belong to the immunoglobulin-like superfamily or the tumour necrosis factor receptor superfamily. Agonistic or antagonistic monoclonal antibodies targeting these co-receptors have the potential to enhance immunity. Furthermore, their activity on the immunosuppressive regulatory T cell populations which are prevalent within many tumours provides an additional rationale for their use as anti-cancer therapies. This review summarizes the interactions between cancer and the immune system, highlighting the ways in which these new classes of immunostimulatory antibodies might enhance anti-tumour immunity and summarizing early clinical experience with their use.