Non-communicable diseases (NCDs) are a leading cause of death and disability, representing 63% of the total death number worldwide. A characteristic phenotype of these diseases is the accelerated aging, which is the result of phenomena such as accumulated DNA damage, telomere capping loss and subcellular irreversible/nonrepaired oxidative damage. DNA damage, mostly oxidative, plays a key role in the development of most common NCDs. The present review will gather some of the most relevant knowledge concerning the presence of DNA damage in NCDs focusing on cardiovascular diseases, diabetes, chronic obstructive pulmonary disease, and neurodegenerative disorders, and discussing a selection of papers from the most informative literature. The challenge of comorbidity and the potential offered by new systems approaches for introducing these biomarkers into the clinical decision process will be discussed. Systems Medicine platforms represent the most suitable approach to personalized medicine, enabling to identify new patterns in the pathogenesis, diagnosis and prognosis of chronic diseases.