The Ras oncoprotein must be modified by farnesyl transferase (FTase) for biological activity. Therefore, inhibition of FTase may offer a means to block ras induced cell transformation. To address this hypothesis, we have introduced antisense and dominant inhibitory FTase expression plasmids into a panel of normal, mutant ras-, and mos- transformed rodent fibroblasts in an effort to genetically suppress FTase activity. Antisense FTase constructs reduced colony formation efficiency approximately 29% in normal and approximately 41% in ras-transformed cells relative to control plasmids. In contrast, antisense FTase plasmids did not exhibit a statistically significant effect on colony formation efficiency in mos-transformed transfectants. FTase alpha N199K is a mutant form of the alpha subunit of FTase that exhibits dominant inhibitory activity versus native FTase. Only mos-transformed transfectants exhibited expression of alpha N199K RNA in 15 of 16 fibroblast lines that were randomly selected and characterized. Our data suggest that genetic inhibition of FTase may result in a selection against animal cell growth.