The lack of effective conventional therapies for the treatment of advanced stage melanoma has stimulated interest in the application of novel strategies for the treatment of patients with malignant melanoma. Because of its expression in a large percentage of melanoma lesions and its restricted distribution in normal tissues, the high molecular weight-melanoma-associated antigen (HMW-MAA), also known as the melanoma chondroitin sulfate proteoglycan (MCSP), has been used to implement immunotherapy of melanoma. The potential clinical relevance of HMW-MAA/MCSP has stimulated investigations to characterize its structural properties and biological function in melanoma cells. Over the last 10 years, the field of HMW-MAA/MCSP research has seen tremendous growth. Specifically, a significant amount of information has been accumulated regarding (1) the structural characteristics of the HMW-MAA/MCSP, (2) its role in the biology of melanoma cells, and (3) the potential molecular mechanisms underlying the association between HMW-MAA/MCSP-specific immunity and survival prolongation in melanoma patients immunized with HMW-MAA/MCSP mimics. In this review, we summarize the characteristics of the HMW-MAA/MCSP in terms of its structure, antigenic profile, tissue distribution, and similarities with its counterparts in other animal species. Additionally, we discuss the role the HMW-MAA/MCSP plays in melanoma cell biology with emphasis on the recently identified signal transduction pathways triggered by the HMW-MAA/MCSP. Finally, we discuss the potential molecular mechanisms underlying the beneficial effect of anti-HMW-MAA/MCSP antibodies on the clinical course of the disease in patients with melanoma.