Comparison of the predicted amino acid sequences of different members of the ras family in vertebrates has shown that the N-terminal 120 residues are highly conserved while the C terminus is variable. To test the possible role of the variable residues in cell transformation, chimeras were constructed containing the N-terminal 111 amino acids of the human Ha-ras EJ oncogene and the C terminus of two Drosophila ras genes. We show that one of these constructs which has only 20 conserved residues between positions 121 and 189, can transform rat-1 cells, and the transformed cells are capable of inducing lethal tumors in rats. The second construct containing the C terminus of another Drosophila ras gene exhibits a transforming capacity as well, but only after linkage to a viral transcriptional promoter. These results show that the majority of residues within the C terminus can be replaced without abolishing the transforming potential of p21 ras.