Activation of the N-ras gene by point mutations occurs in about 15 % of all human melanomas. Using recently established melanoma severe combined immunodeficiency-human mouse xenotransplantation models, here we further investigate the biological significance of these mutations. We demonstrate that activated N-ras significantly contributes to the chemoresistance of human melanoma both in vitro and in vivo by blocking apoptosis. Overexpression of wild-type N-ras had no such effects. With antisense oligonucleotides and farnesyltransferase inhibitors, tools capable of blocking Ras function on the therapeutic horizon, our observation that activated N-ras is not a bystander but a factor worth targeting to improve therapeutic outcome in melanoma gains additional importance.