The melanoma antigen (MAGE) proteins are conserved in all eukaryotes and have expanded from a single gene to more than 40 genes in mammals. While some MAGEs are ubiquitously expressed, the majority are restricted to germ cells and often aberrantly re-activated in multiple cancer types. Much of the initial research on MAGEs focused on exploiting their antigenicity to target them with cancer immunotherapy, while the physiological function of these proteins remained overshadowed. Our discoveries shed the first insights into their physiological role and provided a conceptual breakthrough by showing that MAGEs evolved to protect germ cells against stress and when hijacked by cancer promote oncogenic activity. This opened floodgates in terms of characterizing novel stress-protective pathways, understanding their role in therapy resistance, and improving therapeutic approaches to target them in cancer. In all, we leverage the unique position of MAGE proteins at the intersection of cancer and spermatogenesis to uncover novel mechanisms that evolved to protect mammalian germline against stress, discover how and why they were co-opted in cancer. Ultimately, we want to apply the insights learned for the advancement of cancer treatment and fertility preservation to benefit human and animal patients.