To obtain insight into the mechanisms of tumor progression in cutaneous malignant melanoma (CMM), and in search of new prognostic markers, gene expression profiling on a series of CMMs with known follow-up was performed. We identified an expression signature of 254 genes with prognostic significance, with a predictive accuracy comparable to that obtainable from tumor thickness and ulceration. Most of these genes were correlated with thickness, thereby stressing the importance of thickness in the prognosis of CMM. On immunohistochemistry, eight new prognostic markers were identified, of which three (mini-chromosome maintenance proteins 3, 4 and 6) had independent prognostic value. These data provide new information regarding CMM progression. As several of the progression-related genes encode molecules that are the target of established or experimental therapies, our results may hopefully contribute to the treatment of end-stage CMM patients.