Significance Lung cancer is unique among solid tumors as robust natural killer (NK) cell function correlates with resistance to disease. Here we describe that NK cell education by major histocompatibility class I (MHCI) leads to the up-regulation of NKG2D- and NKp46-activating receptors that recognize lung cancer. We further demonstrate that upon activation NK cells down-regulate the expression of the Ly49C/I inhibitory receptor, thus eliminating target interference by MHCI. Our findings are significant based on the demonstration that NK cells that arise in an MHCI ^+/+ environment present a substantial barrier to the growth of lung cancer, and expression of both activating and inhibitory receptors is not fixed but varies based on environmental context.