Dysfunctional virus-specific T cells are a hallmark of many chronic viral infections. Recent studies have implicated the inhibitory PD-1/PD-L1 pathway with the functional impairment of T cells. In this respect, we will review the latest research on PD-1/PD-L1 pathway and T-cell exhaustion in the context of human chronic hepatitis B and C virus infections. We will also discuss the therapeutic potential of PD-1 blockade and how it may be enhanced through the modulation of other co-stimulatory/inhibitory pathways.