Melanoma cells escape transforming growth factor-beta (TGFbeta)-mediated growth inhibition by expressing the Smad (mothers against decapentaplegic homolog, Drosophila) inhibitors Ski and Sno. Here, we demonstrate that melanoma inhibitory activity (MIA) influences the expression of these inhibitors. A Smad responsive reporter construct was activated after TGFbeta1 treatment in the MIA-deficient cell clones but not in the parental cell line. According to this finding, the TGFbeta target genes JunB and Id-1 showed a strong induction of expression. Additional analyses revealed that Ski and Sno, repressors of TGFbeta/SMAD signaling, are not expressed in the MIA-deficient cells but in the parental cell line HMB2 and the mock control. Further investigation showed that Ski and Sno expression might be regulated via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling cascade. Treatment of HMB2 cells with a MEK inhibitor revealed a reduction of Ski and Sno expression, which leads to the conclusion that, in our melanoma cell model, Ski and Sno expression is regulated via MAPK/ERK signaling.