Abstract: Metastatic melanomas are highly resistant to radiation and chemotherapy from the earliest stages, which is a major factor in poor clinical outcomes. Activated leukocyte adhesion molecule (ALCAM)/CD166 was the gene that showed the highest correlation with detachment-induced chemoresistance. SiRNA-mediated depletion or antibody blocking of ALCAM specifically inhibited the increase in chemoresistance after detachment. This antibody also improved chemotherapeutic responses in a mouse xenograft model of human melanoma. Previous studies identified ALCAM as a marker for tumor aggressiveness and poor prognosis, and as a marker for “stemness”. Targeting ALCAM may therefore represent a novel approach for treatment of otherwise intractable melanomas. It was also found that stimulating integrin signaling enhanced chemosensitivity of melanoma to chemotherapeutic agents.