The human genome encodes more than 300 potential immune inhibitory receptors. The reason for this large number of receptors remains unclear. We suggest that inhibitory receptors operate as two distinct functional categories: receptors that control the signalling threshold for immune cell activation and receptors involved in the negative feedback of immune cell activation. These two categories have characteristic receptor expression patterns: 'threshold' receptors are expressed at steady state and their expression remains high or is downregulated upon activation, whereas 'negative feedback' receptors are induced upon immune cell activation. We use mathematical models to illustrate their possible modes of operation in different scenarios for different purposes. We discuss how this categorization may impact the choice of therapeutic targets for immunotherapy of malignant, infectious and autoimmune diseases.