Cancer care has witnessed remarkable progress in recent decades, with a wide array of targeted therapies and immune-based interventions being added to the traditional treatment options such as surgery, chemotherapy, and radiotherapy. However, despite these advancements, the challenge of achieving high tumor specificity while minimizing adverse side effects continues to dictate the benefit-risk balance of cancer therapy, guiding clinical decision making. As such, the targeting of cancer testis antigens (CTAs) offers exciting new opportunities for therapeutic intervention of cancer since they display highly tumor specific expression patterns, natural immunogenicity and play pivotal roles in various biological processes that are critical for tumor cellular fitness. In this review, we delve deeper into how CTAs contribute to the regulation and maintenance of genomic integrity in cancer, and how these mechanisms can be exploited to specifically target and eradicate tumor cells. We review the current clinical trials targeting aforementioned CTAs, highlight promising pre-clinical data and discuss current challenges and future perspectives for future development of CTA-based strategies that exploit tumor genomic instability.