Herein, we will discuss about the protease-mediated cleavage of NKG2D ligands on cancer cells in response to stress stimuli focusing our attention on: (i) the role played by ADAM10 in this process; (ii) the mechanisms regulating ADAM10 expression and activity in cancer cells; (iii) the implications of NKG2D ligand shedding in the course of cancer therapy. This evidence concerns the gene ADAM10 and cancer.