Malignant melanoma is an unpredictable, aggressive disease with the fastest growing incidence among all cancers. Its high metastatic potential and tendency to relapse are poorly prevented by existing systemic therapy. In spite of apparent eradication through treatment in accordance with the newest clinical guidelines, the disease is likely to recur. Cancer stem cells, with their plasticity, self-renewal ability and drug resistance represent a highly probable culprit for these relapses. This special subpopulation of cancer cells is relatively small in number, but harbors uncanny tumor initiating, invasion and metastasis potential. While their very existence remains a controversy among research groups, the evidence for their prominent role in malignancies has multiplied with the number of studies performed in this area in the past few years. Unraveling the molecular mechanisms behind these cells’ unique abilities could lead to novel strategies in the diagnostics and treatment of malignant melanoma. Since the diagnostic value of genetic testing has proven questionable, certain recently discovered biomarkers offer a promising alternative. They may also serve as targets for immunotherapy and reprogramming that could lead to improving patient survival and potentially finally curing this insidious disease.