Whether a cell is normal or cancerous could hinge on the presence or absence of a few key molecules. Tumor viruses or chemical carcinogens could convert normal cells to transformed cells (i.e., tumor cells) by preventing or altering the expression of 1 or several genes whose products are necessary for normal cellular metabolism. Since this explanation of transformation was considered plausible, cell biologists spent years looking for proteins that are present (or absent) in all normal cells, regardless of the kind of cell, and absent (or present) in all transformed cells, regardless of the means of transformation. About 1.5 yr ago, investigators at 6 laboratories, using 4 experimental techniques, independently discovered that 1 gene product, a large cell surface protein, is lost when cells are transformed. This large external transformation sensitive (LETS) protein has a molecular weight of 250,000, contains the sugar galactose and is found on normal cells from a wide variety of species, including human beings, rats and chickens. Some investigators found that when normal cells are exposed to enzymes that strip off their LETS proteins, they can lose control of their growth and biochemically and morphologically resemble transformed cells. To settle the issue of whether the removal of LETS causes transformation, it will be necessary to add purified LETS protein to transformed cells and see if the cells revert to normal. If the cells revert to normal, it will be necessary to see if the reversion can be blocked by antibodies to LETS. Hynes and Yamada succeeded in extracting and purifying large quantities of LETS from chick cells and in obtaining antibodies to this purified protein. Both plan to add purified LETS protein to transformed cells. Whether LETS protein has a role in transformation still remains to be determined. It now seems unlikely that studies of this protein can provide a simple answer to the question of how transformation occurs.