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Traditionally neglected and frequently excluded from large-scale genomic studies, the Y chromosome is now emerging as a potential Achilles' heel of cancers in men. Recent evidence has suggested that loss of this chromosome - a phenomenon known as loss of Y chromosome (LOY) - is not a silent event, but rather an active driver that promotes tumor progression through loss of tumor suppressor genes, increasing tumor growth and enabling immune evasion. Importantly, LOY creates loss of heterozygosity of paralogous genes on the X chromosome, a vulnerability that can potentially be therapeutically exploited. The exact mechanisms of LOY in cancer, and the utility of LOY as a biomarker and therapeutic target, are open questions for the emerging field of Y chromosome-focused cancer research.