Natural killer (NK) cells are lymphoid effector cells possessing spontaneous cytolytic activity against a variety of tumour targets. The fact that NK cells pre-exist at high frequency and require no lengthy activation, and the observation that differentiated and metastatic tumour cells often have a decreased sensitivity to NK cytolysis have led to the hypothesis that these cells may be involved in the earliest stages of antitumour surveillance. Central to this model is the prediction that NK sensitivity must arise during cellular transformation. To test this prediction directly, we have constructed a vector containing the transforming gene from the EJ bladder carcinoma cell line under the transcriptional control of the mouse metallothionein-I promoter. When induced with heavy metal ions, mouse fibroblast lines containing this vector become dramatically sensitive to NK-mediated cytolysis concomitant with the expression of the cellular Harvey ras (c-Ha-ras) p21 protein and with cellular transformation.