The human homologue of the v-sis oncogene encodes one chain of human platelet-derived growth factor (PDGF-2). Previous studies have shown that expression of the coding sequence for this growth factor induces malignant transformation of NIH/3T3 cells. We demonstrate the detection of sis/PDGF-2 products indistinguishable from functional PDGF-2 homodimers in human tumor cells. These findings support the concept that expression of the sis/PDGF-2 product in human cells responsive to its proliferative actions can be an important step in the processes leading to malignancy. Unlike sis/PDGF-2, which remains tightly cell-associated, another growth factor, termed transforming growth factor alpha (TGF alpha), is actively secreted. Expression vectors for the TGF alpha coding sequence failed to induce primary transformed foci upon transfection of NIH/3T3 cells despite high levels of TGF alpha synthesized by these cells. Moreover, transfectants selected for secretion of high levels of TGF alpha failed to form colonies on contact inhibited NIH/3T3 monolayers or to induce tumors upon inoculation of nude mice. Thus, the ability of a growth factor to induce autonomous in vitro or in vivo growth is dependent upon more than expression of cognate receptors by the cell in which it is synthesized.