Normal human WI-38 [embryo lung] cells can be protected from killing by hydroxyurea if proliferation is arrested during drug treatment. This protection was demonstrated in cells arrested by density dependent inhibition and 3''-amino-3''-deoxy-N6,N6-dimethyladenosine (puromycin aminonucleoside). In contrast, VA-13 cells (an SV-40 transformed clone of WI-38) were not arrested under these conditions, and continued to be sensitive to hydroxyurea. These results suggest that a search for agents that selectively and reversibly inhibit normal cycling human cells might lead to an enhancement of differential tumor toxicity.