Melanoma is a cancer characterized by predisposition to natural and induced immune rejection. The occurrence of this phenomenon, however, remains sporadic and capricious while there is no clear understanding of the chain of events responsible. With the progression of the understanding of the molecular immunology of melanoma during the last decade, several theories suggesting immune tolerance (inadequate immune response) and/or immune escape (adaptation of cancer cells to a vigorous immune pressure) as possible modulators of melanoma growth have emerged. As the number of these hypotheses, mostly based on molecular or pre-clinical models, has increased exponentially, the relevance of each individual one has been conversely decreasing leaving the observer without confidence that a theory likely to explain this phenomenon can be soon formulated. In this review, we will discuss a direct approach whereby new theories might be identified by direct observation of human phenomena as they occur by depiction of molecular portraits of melanoma lesions using global transcript analysis.