Five random subclones of the rat fibroblast line F2408 vary in their frequency of transformation by the unrelated Kirsten murine sarcoma virus and Abelson murine leukemia virus. The same pattern of sensitivity is displayed when the cells are induced to anchorage-independent growth (transformed) by epidermal, platelet-derived, and sarcoma growth factors, or by whole serum. Our results demonstrate that a growth factor's ability to render cells anchorage independent is not unique to transforming growth factors, but common to many growth factors; anchorage-independent growth is a function of the total growth factor concentration in the medium; cells vary in their inherent responsiveness to growth-factor-induced anchorage-independent growth; and cells resistant to growth-factor-induced anchorage-independent growth are also resistant to transformation by a variety of tumor viruses. We conclude that the way a cell responds to growth factors plays a central role in the expression of the transformed phenotype.