CD8⁺ tissue-resident memory T (T_RM) cells play crucial roles in defense against infections and cancer and have been implicated in autoimmune diseases such as psoriasis. In mice and humans, they exist in all nonlymphoid organs and share key characteristics across all tissues, including downregulation of tissue egress and lymph node homing pathways. However, recent studies demonstrate considerable heterogeneity across T_RM cells lodged in different tissues – linked to the activity of tissue-specific molecules, including chemokines, cytokines, and transcription factors. Current work indicates that transforming growth factor (TGF)-β plays a major role in generating T_RM heterogeneity at phenotypic and functional levels. Here, we review common and unique features of T_RM cells in different tissues and discuss putative strategies aimed at harnessing T_RM cells for site-specific protection against infectious and malignant diseases.