A study published in *Nature* (2008) identifies a subpopulation of human malignant melanoma-initiating cells (MMIC) defined by the expression of the chemoresistance mediator ABCB5. These cells are capable of self-renewal and differentiation, and their presence correlates with clinical melanoma progression. The study shows that targeting ABCB5-positive cells inhibits tumor growth and that these cells are more tumorigenic than ABCB5-negative bulk populations. In xenotransplantation experiments, ABCB5-positive cells re-established tumor heterogeneity and demonstrated a higher capacity for self-renewal and differentiation. In vivo genetic lineage tracking confirmed that ABCB5-positive cells generate both ABCB5-positive and ABCB5-negative progeny, while ABCB5-negative cells give rise to ABCB5-negative cells. A monoclonal antibody targeting ABCB5 was shown to inhibit tumor growth and formation in melanoma xenografts, indicating that targeting ABCB5-positive cells could be a strategy for cancer therapy. The study highlights the importance of ABCB5 as a molecular marker for MMIC and suggests that targeting these cells may offer new therapeutic approaches for melanoma. The findings also suggest that ABCB5-positive cells may be responsible for the progression and chemoresistance of advanced melanoma. The study provides insights into the tumor hierarchy and the role of ABCB5 in melanoma progression and chemoresistance.A study published in *Nature* (2008) identifies a subpopulation of human malignant melanoma-initiating cells (MMIC) defined by the expression of the chemoresistance mediator ABCB5. These cells are capable of self-renewal and differentiation, and their presence correlates with clinical melanoma progression. The study shows that targeting ABCB5-positive cells inhibits tumor growth and that these cells are more tumorigenic than ABCB5-negative bulk populations. In xenotransplantation experiments, ABCB5-positive cells re-established tumor heterogeneity and demonstrated a higher capacity for self-renewal and differentiation. In vivo genetic lineage tracking confirmed that ABCB5-positive cells generate both ABCB5-positive and ABCB5-negative progeny, while ABCB5-negative cells give rise to ABCB5-negative cells. A monoclonal antibody targeting ABCB5 was shown to inhibit tumor growth and formation in melanoma xenografts, indicating that targeting ABCB5-positive cells could be a strategy for cancer therapy. The study highlights the importance of ABCB5 as a molecular marker for MMIC and suggests that targeting these cells may offer new therapeutic approaches for melanoma. The findings also suggest that ABCB5-positive cells may be responsible for the progression and chemoresistance of advanced melanoma. The study provides insights into the tumor hierarchy and the role of ABCB5 in melanoma progression and chemoresistance.