The utility of different models to identify cancer stem cells continues to be a subject of intense debate. Here, we summarize recent efforts to characterize intra-tumoral heterogeneity of melanoma and delineate key questions for future studies. Within a developing or already established tumor microenvironment, we propose that continuous tumor maintenance is assured by specific sub-populations whose phenotype is not static but instead is dynamically regulated. These small and temporarily distinct sub-populations likely have critical roles in tumor progression. They are important therapeutic targets, but only in the context of combination therapies, that also eliminate the bulk of the tumor.