Over the past decade, it has become clear that there is an important subset of memory T cells that resides in tissues—tissue-resident memory T (T_RM) cells. There is an emerging understanding that T_RM cells have a role in human tissue-specific immune and inflammatory diseases. Furthermore, the nature of the molecular signals that maintain T_RM cells in tissues is the subject of much investigation. In addition, whereas it is logical for T_RM cells to be located in barrier tissues at interfaces with the environment, these cells have also been found in brain, kidney, joint and other non-barrier tissues in humans and mice. Given the biology and behavior of these cells, it is likely that they have a role in chronic relapsing and remitting diseases of both barrier and non-barrier tissues. In this Review we discuss recent insights into the biology of T_RM cells with a particular focus on their roles in disease, both proven and putative.