Immunological memory, defined as the ability to respond in an enhanced manner upon secondary encounter with the same pathogen, can provide substantial protection against infectious disease. Different populations of memory T cells that are retained after primary infection contribute to the enhanced protection. An important component of acquired T-cell driven immunity derives from resident memory T cells (Trm). These Trm form local populations in and directly underneath the epithelial layer of skin, gut, lungs and other relevant entry sites of pathogens. This strategic position enables them to directly respond upon reinfection with the production of pro-inflammatory cytokines and cytotoxic molecules to counter the invading pathogens. Trm have not only been found essential in protection against reinfection, but they also appear to substantially improve disease outcome in cancer patients. For these reasons, we aim to improve our understanding of the differentiation and the re-activation of Trm to ultimately develop approaches to wield these memory T cells for therapy of cancer patients.