The controlled orchestration of immune responses is a vital feature of cellular immunity in a system that must be able to reliably distinguish self from non-self. Contrary to early beliefs, peptide recognition by T cells exhibits a relatively high level of promiscuity. The requirement for a second signalling event to be present in addition to that provided by T cell receptor ligation for T cell activation to proceed helps to prevent inappropriately directed responses. An expanding array of co-stimulatory or inhibitory signalling receptors and ligands are now recognised to be involved in the control of the crucial decisions made determining the activation, expansion, and effector functions of responding cells, and ultimately the final targeting and execution of these functions. Tight regulation of the temporal and spatial organisation of receptor/ligand expression, combined with both forward and reverse signalling, endows an extraordinary elegance to these co-stimulatory pathways. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses. The understanding of its relevance in a variety of physio-pathological circumstances is now yielding a number of potential targets for therapeutic manipulation, and such immunological molecular adjuvants are beginning to enter clinical trials.