The activating killer cell lectin-like receptor NKG2D plays a key role in the natural killer (NK) cell-mediated lysis of tumours and infected cells. Unlike other receptors, the ligands recognised by NKG2D are 'induced-self' ligands on stressed cells. This system requires precise regulation because inappropriate expression of NKG2D ligands might compromise NK cell activation. For therapeutic purposes it is essential to understand the mechanisms that regulate the expression and function of the NKG2D system. This review focuses on the importance of the signalling pathways involved in the regulation of the NKG2D receptor and its ligand expression in arming the immune response against infected or tumour cells and for the identification of new molecular targets and therapeutic strategies.