Genomic integrity is strongly protected by cellular surveillance mechanisms, but its lack of regulation facilitates damage to the DNA molecule, genomic instability, and pathological alteration of the cells. As a consequence, diseases such as ageing and cancer develop. In this review, we will address the main findings on genomic instability, with a special focus on the causes of instability and cellular responses. We will also discuss advances based on the exploitation of this distinctive, aimed at the treatment of cancers and other diseases.