MAGE-A proteins constitute a sub-family of Cancer-Testis Antigens which are expressed mainly, but not exclusively, in germ cells. They are also expressed in various human cancers where they are associated with, and may drive, malignancy. MAGE-A proteins are highly immunogenic and are considered as potential targets for cancer vaccines and/or immuno-therapy. Moreover, recent advances in our understanding of their molecular pathology have revealed interactions that offer potential as therapeutic targets. Here we review recent progress in this area and consider how these interactions might be exploited, especially for the treatment of malignant cancers for which available treatments are inadequate.