The natural killer (NK) group 2 member D (NKG2D) is an activating immune receptor expressed on NK cells, cytotoxic T cells and a subset of other T cells. It has an important role in the recognition and lysis of a variety of infected and tumor cells. Despite significant gains in our understanding of NKG2D, the relevance of NKG2D and its ligands in human diseases has only recently started to emerge. Here, we present an overview of the recent advances in NKG2D biology, discuss the expression of NKG2D ligands in cancer patients and evaluate the diagnostic and prognostic potential of NKG2D ligands.