<p>Genomic instability in tumors, one of the hallmarks of cancer, results from an accumulation of DNA damage that promotes tumor progression and metastasis. It influences cellular processes and the tumor microenvironment and promotes immune evasion and resistance to therapy. Some molecular mechanisms such as “BRCAness” (starting point for PARP inhibitors), microsatellite instability (starting point for immunotherapy), and epigenetics (starting point for DNA methyltransferase inhibitors and histone modifiers) can be used therapeutically and have already been successfully introduced into clinical practice. Many other therapeutic approaches, e.g., modulation of chromosomal instability, which can only be detected through high-end diagnostic approaches such as next-generation sequencing, are still undergoing (pre-)clinical testing. The development of resistance to genotoxic therapy and treatment-associated toxicities represent major challenge.</p>