Adoptive cell therapy (ACT) using melanoma-specific cytotoxic T cells can promote remission in patients with metastatic melanoma, but the tumours often return; this study offers an explanation why. The authors used both mouse and human systems to show that tumour necrosis factor (TNF) promotes the loss of melanoma-associated antigens, such as MART1 or gp100, from melanoma cells. This was a reversible phenomenon, as the melanoma cells reacquired expression of gp100 when transplanted into other hosts. Although the TNF-conditioned melanoma cells could no longer be recognized by T cells specific for melanocytic antigens, they could be targeted by T cells specific for other mutated proteins. Therefore, in future, the efficacy of ACT could be improved by targeting both melanocytic and non-melanocytic antigens.