T cell surveillance of tissues is spatially organized: circulating memory T cells perform surveillance of secondary lymphoid organs while tissue-resident memory T cells act as sentinels in barrier tissues. In the context of infection, tissue-resident memory T cells survive long term in barrier tissues and are poised to respond to re-encounter of infectious agents. The activity of such tissue-resident T cells is regulated by the PD-1 and CTLA-4 inhibitory receptors targeted by cancer immunotherapies. This review investigates the hypothesis that T cells with a tissue residency program play an important role in both protective anti-tumor immunity and immune-related adverse events (irAEs) of immune checkpoint blockade (ICB). A series of translational studies have demonstrated that a higher density of tissue-resident T cells within tumors is associated with favorable survival outcomes in a diverse range of cancer types. Tissue-resident T cells have also been implicated in clinical response to immune checkpoint blockade, and dynamic tracking of T cell populations in pre- and on-treatment tumor samples demonstrated that T cells with a tissue residency program responded early to ICB. Investigation of colitis and dermatitis as examples of irAEs demonstrated that tissue-resident memory T cells were reactivated at these epithelial sites, resulting in a highly cytotoxic state and secretion of inflammatory cytokines IFNγ and TNFα. It will therefore be important to consider how a tissue residency program can be enhanced to promote T cell-mediated tumor immunity while preventing the development of irAEs.