Interest in the use of cell-free nucleic acids (CFNAs) as clinical non-invasive biomarker panels for prediction and prevention of multiple diseases has greatly increased over the last decade. Indeed, circulating CFNAs are attributable to many physiological and pathological processes such as imbalanced stress conditions, physical activities, extensive apoptosis of different origin, systemic hypoxic-ischemic events and tumour progression, amongst others. This article highlights the involvement of circulating CFNAs in local and systemic processes dealing with the question, whether specific patterns of CFNAs in blood, their detection, quantity and quality (such as their methylation status) might be instrumental to predict a disease development/progression and could be further utilised for accompanying diagnostics, targeted prevention, creation of individualised therapy algorithms, therapy monitoring and prognosis. Presented considerations conform with principles of 3P medicine and serve for improving individual outcomes and cost efficacy of medical services provided to the population.