The potency of the T cell response against pathogens or cancer cells is determined by the signalling output from two distinct classes of immune receptors: the T-cell receptor and co-receptors, which includes activating and inhibitory checkpoint receptors such as CD28 or PD-1 and CTLA-4, respectively. Here, we will provide an update on our latest work in targeting T-cell receptors and inhibitory receptors to modulate T cell responses.