Cutaneous melanoma still represents a paradox among all solid tumors. It is the cancer for which the best prognostic markers ever identified in solid tumors are available, yet there is very little understanding of their biological significance. This review focuses on recent biological data that shed light on the clinical-biological correlations underlining the 2010 American Joint Committee on Cancer (AJCC) melanoma staging system. A major challenge is to replace outcome clustering based on artificial biomarker breakpoints by a continuous multidimensional prognostic model. Major improvement will come from shared computerized tools that allow the generation of continuous likelihood scores for diagnosis, prognosis, and response prediction. This will lead to the development of platforms which can be used by scientists from different fields to integrate and share high-quality data in the pre-competitive setting and generate new probabilistic causal models.