Malignant transformation of melanocytes may be associated with changes in the expression of major histocompatibility complex (MHC) HLA class I antigens. Interest in the characterization of abnormalities in the expression of MHC class I by melanoma cells has been rekindled by the current emphasis on the application of T-cell-based immunotherapy to melanoma. Here, Soldano Ferrone and Francesco Marincola review defects in class I expression as described in melanoma cells, as well as the molecular mechanisms, functional significance and clinical implications of such defects.