The constitutive activity of a number of growth and cell survival pathways are thought to contribute to the inherent resistance of melanoma to chemotherapy and radiotherapy. Many of these pathways are driven through the small GTPase Ras. Novel drugs such as the farnesyl transferase inhibitors (FTIs) and farnesyl thiosalicylic acid (FTS) interfere with the signaling of oncogenic Ras. The aim of our study was to assess the anti‐tumour activity of the FTI SCH66336 in melanoma and to assess whether SCH66336 and FTS could modulate chemoresistance in melanoma cells. SCH66336 had marked anti‐proliferative activity in both human and mouse melanoma cell lines, but not in non‐transformed NIH 3T3 cells. The anti‐proliferative activity of SCH66336 was due to G1‐phase cell cycle arrest and retinoblastoma protein inactivation, followed by apoptosis. Cisplatin, when administered alone, induced little apoptosis. In combination with cisplatin, both FTS and SCH66336 markedly enhanced the level of cisplatin‐induced apoptosis, an effect that was associated with enhanced G2/M cell cycle arrest. Pharmacological inhibitors of either ERK or PI‐3 kinase/Akt did not mimic the chemosensitising activity of either SCH66336 or FTS. In summary, our study demonstrates that SCH66336 has good in vitro anti‐tumour activity in both human and mouse melanoma cell lines, and suggests that Ras antagonists could be useful in overcoming chemoresistance to cisplatin in melanoma. © 2003 Wiley‐Liss, Inc.