•Immune cells combating chronic infection express numerous ‘check point’ receptors in human patients.•Inhibition of these receptors restores the function of exhausted T cells in chronically infected humans and animals.•Initial case reports in humans suggest targeting checkpoint inhibitors in HBV, HCV, and HIV could repress viral loads.•Newly identified inhibitory receptors may synergize to induce exhaustion, and therefore multiple pathways could be targeted to facilitate immunity. The recent successes of immune check point targeting therapies in treating cancer patients has driven a resurgence of interest in targeting these pathways in chronically infected patients. While still in early stages, basic and clinical data suggest that blockade of CTLA-4 and PD-1 can be beneficial in the treatment of chronic HIV, HBV, and HCV infection, as well as other chronic maladies. Furthermore, novel inhibitory receptors such as Tim-3, LAG-3, and TIGIT are the potential next wave of check points that can be manipulated for the treatment of chronic infection. Blockade of these pathways influences more than simply T cell responses, and may provide new therapeutic options for chronically infected patients.