Recent clonal studies of spontaneous neoplastic transformation in cell culture indicate that it develops at confluence in a small minority of individual clonal populations before it does in the uncloned parental culture. Either preferential selection of spontaneous variants or genetic destabilization in clones can be inferred to explain the result. In the present experiments, using a subline of NIH 3T3 cells that is relatively refractory to transformation, we demonstrate unequivocally that transformed foci appear under selective conditions in some clones long before there is any sign of neoplastic change in the polyclonal culture from which they were derived. Because the transformed cells that appear in the susceptible clones are not inhibited in the size or number of foci formed on a confluent background of the uncloned parental population, the genetic events underlying transformation must occur much less frequently in the latter. This disparity can be accounted for by the much larger number of selectable cells in the susceptible clones at confluence than in the parental culture, where such cells are a minority. The preferential transformation exhibited by experimental isolation and expansion of susceptible clones accords with evidence from various sources that neoplastic transformation in culture is a multistep process dependent primarily on selection of spontaneously occurring genetic variants. There is no necessity to posit a significant role for genetic destabilization in neoplastic transformation. These considerations bolster computer models of human cancer that implicate selective expansion of rogue clones rather than genetic instability as the driving force in the origin of most tumors. Both the genetics of the selected clone and the epigenetics of the selective environment would then contribute to tumor development.