Stem memory T cells (TSCM) have been described in mice, non-human primates and in humans, constituting approximately 2-4% of the total CD4(+) and CD8(+) T-cell population in the periphery. TSCM represent the earliest and long-lasting developmental stage of memory T cells, displaying stem cell-like properties, and exhibiting a gene profile between naïve and central memory T cells. Their self-renewal capacity and long-term survival has sparked interest in the cancer and human immunodeficiency virus (HIV) fields. How and when the formation of TSCM occurs during the immune response to pathogens and the therapeutic potential of these cells are currently being investigated. This review will explore the potential role of TSCM to be used as, or targeted by, immunotherapies and vaccines for treatment of cancer and HIV.