The in-depth understanding of skin resident memory CD8 T lymphocytes (T ) may help to uncover strategies for their manipulation during disease. We investigated isolated T from healthy human skin, which expressed the residence marker CD69, and compared them to circulating CD8 T cell populations from the same donors. There were significantly increased proportions of CD8 CD45RA CD27 T cells in the skin that expressed low levels of killer cell lectin-like receptor G1 (KLRG1), CD57, perforin and granzyme B. The CD8 T in skin were therefore phenotypically distinct from circulating CD8 CD45RA CD27 T cells that expressed high levels of all these molecules. Nevertheless, the activation of CD8 T with T cell receptor (TCR)/CD28 or interleukin (IL)-2 or IL-15 in vitro induced the expression of granzyme B. Blocking signalling through the inhibitory receptor programmed cell death 1 (PD)-1 further boosted granzyme B expression. A unique feature of some CD8 T cells was their ability to secrete high levels of tumour necrosis factor (TNF)-α and IL-2, a cytokine combination that was not seen frequently in circulating CD8 T cells. The cutaneous CD8 T are therefore diverse, and appear to be phenotypically and functionally distinct from circulating cells. Indeed, the surface receptors used to distinguish differentiation stages of blood T cells cannot be applied to T cells in the skin. Furthermore, the function of cutaneous T appears to be stringently controlled by environmental signals in situ.