The gp240 antigen (also known as the high-molecular weight melanoma-associated antigen) is well expressed on a high percentage of melanoma cell lines and on melanoma tumor biopsy specimens. It is postulated that HMW-MAA contributes to the malignant phenotype of melanoma cells via enhancement of their spreading, invasion, and migration. The expression of HMW-MAA in adult tissues is restricted to hair follicles, basal cells of the epidermis, endothelial cells, and activated pericytes. Given its expression on the majority of melanoma lesions with limited inter- and intra- lesional heterogeneity and its restricted expression on normal tissues, HMW-MAA represents a clinically attractive target for CAR-based immunotherapy.