Historically, human NK cells have been identified as CD3(-)CD56(+)CD16(±) lymphocytes. More recently it has been established that CD57 expression defines functionally discrete sub-populations of NK cells. On T cells, CD57 expression has been regarded as a marker of terminal differentiation and (perhaps wrongly) of anergy and senescence. Similarly, CD57 expression seems to identify the final stages of peripheral NK cell maturation; its expression increases with age and is associated with chronic infections, particularly human cytomegalovirus infection. However, CD57(+) NK cells are highly cytotoxic and their presence seems to be beneficial in a number of non-communicable diseases. The purpose of this article is to review our current understanding of CD57 expression as a marker of NK cell function and disease prognosis, as well as to outline areas for further research.