The activation of naive T cells requires two signals from the antigen presenting cells (APC). Firstly, an antigen specific signal which is triggered by the binding of the T cell receptor (TCR) to the peptide-MHC complex, and secondly, antigen nonspecific signals initiated through a set of co-signalling receptors. Co-signalling molecules are cell-surface glycoproteins that play essential roles for the communication of a T cell with virtually all other host cells by modulating and fine-tuning TCR signals. On the basis of their functional outcome, co-signalling molecules can be divided into co-stimulators and co-inhibitors, which promote or suppress T-cell activation, respectively. By expression at the appropriate time and location, co-signalling molecules positively and negatively control the priming, growth, differentiation and functional maturation of a T-cell response. In this article, I overview property of co-signaling molecules in the CD28- and TNFR family and discuss their potential functional relationships with each other. In addition, role of these co-signalling molecules in various diseases, such as autoimmune diseases, graft rejection, allergy, inflammatory bowel disease, and cancer, and the therapeutic potential of targeting these molecules to enhance or curtail an ongoing immune response in these diseases are discussed.