Genomic instability (GIN) is a central feature of cancer and ageing that if prevented would lead to disease improvement thus representing an important therapeutic avenue. Our cells are constantly bombarded by external (e.g. ionizing radiations) and internal (e.g. replication stress) factors that create DNA lesions (DNA damage). These injuries can range from simple nicks to highly toxic double-strand DNA breaks (DSBs) and are counteracted by the DNA damage response (DDR). The DDR comprises a collection of signal transduction pathways that sense DNA damage and trigger appropriate responses such as DNA repair, temporary or permanent cell cycle arrest (senescence), or cell death (apoptosis or autophagy). Failure to implement these responses results in GIN and initiation of diverse pathologies including cancer and ageing. To explore genetic mechanisms of GIN accumulation, we have performed genetic and drug screens aimed at identifying therapeutic opportunities to alleviate disease. Our results show how different nodes in the disease related pathways can be taken advantage off in order to understand cancer cell resistance/relapse to therapies (e.g. in the context of ATM tumour suppressor gene) or delay ageing (e.g. in the context of Hutchinson-Gilford Progeria Syndrome). Moreover, we use these findings to translate our results to mouse models of disease, pushing closer towards considering these avenues in clinical settings. We emphasize there should be a renewed appreciation both for the importance of studying gene interactions and for addressing these questions in a unified, quantitative manner that will aid the diagnosis and treatment of debilitating disease including cancer and ageing.