Previous studies have suggested that transforming growth factor‐beta 1 (TGF‐β1) acts as an autocrine growth inhibitor on normal human melanocytes, while melanoma cells may not respond to this stimulus. The role of other TGF‐β isoforms such as TGF‐β2 and TGF‐β3 remained less well characterized. In the present study, the mRNA and protein levels of all three isoforms of TGF‐β were analyzed in a panel of human melanoma cell lines and in cultures of normal human melanocytes in vitro. Northern analysis showed that the degree of TGF‐β1, ‐β2, ‐β3 mRNA expression varied considerably in melanoma cells, whereas TGF‐β expression was very low in melanocytes. In melanoma cells, secreted amounts of TGF‐β1 and TGF‐β3 were found increased in comparison to normal melanocytes: 615 pg/ml vs. 118 pg/ml and 193 pg/ml vs. 30 pg/ml (mean values). In addition, low levels of TGF‐β2 were detected (mean value: 28 pg/ml). Although TGF‐β secretion increased, the proliferation of melanoma cells was found to be only moderately inhibited by TGF‐β isoforms, in contrast to its strong antiproliferative effect on normal human melanocytes: −15%, −11%, and −18% vs. −52%, −46%, and −50% average inhibition at 0.5 ng/ml TGF‐β1, ‐β2, and ‐β3, respectively. The different efficacy of TGF‐β on melanocyte and melanoma cells was highly significant (P < 0.0001); in addition, TGF‐β–dependent growth inhibition of melanoma cells from primary tumors vs. cells from metastases showed a trend for further decreased response for the metastatic populations (P ≤ 0.075). Measurements of DNA synthesis revealed even more pronounced differences between melanocytes (−86%, −78%, and −80% inhibition, respectively, for TGF‐β1, ‐β2, and ‐β3) and melanoma cells (no inhibition). Our data show loss of responsiveness of melanoma cells to the growth‐inhibitory function of TGF‐β isoforms but not of melanocytes. Although melanoma cells are not growth‐inhibited by all three TGF‐β isoforms, they secrete significantly higher levels of TGF‐β, as compared to melanocytes. The reduced response indicates their escape from TGF‐β surveillance with ongoing tumor progression. J Cell Physiol 178:179–187, 1999. © 1999 Wiley‐Liss, Inc.