Natural killer (NK) cells use receptors such as NKG2D to recognize and eliminate cancer cells that overexpress ligands for these receptors. Deng et al. have studied a mouse NKG2D ligand — MULT1, which is commonly upregulated in primary tumours — and shown that shedding of MULT1 causes NK cell activation and tumour rejection. Secreted MULT1 reverses the desensitization of NK cells caused by membrane-bound NKG2D ligands on tumour-associated cells, such as myeloid cells. Recombinant soluble MULT1 also stimulated tumour rejection in mice, so this could be an approach for cancer immunotherapy.