Air pollution, especially particulate matter (PM), and traffic noise are major intertwined environmental risks. They contribute to the incidence of cardiovascular, cerebrovascular, mental, and metabolic, so-called non-communicable diseases (NCDs). Air pollution contributes to annual premature deaths (0.5 million) and traffic noise to loss of 1.6 million healthy life years in Europe. Critical issues are that noise and PM are underrepresented in clinical guidelines and that European legal exposure limits exceed WHO standards, also due to a limited understanding of knowledge transfer and success metrics. Significant knowledge gaps are related to additive effects of PM and noise, the role of ultrafine particle (UFP), adverse brain-heart axis signaling, and the consequences for vulnerable groups such as high-risk patients and the elderly. We address these critical health issues of traffic noise and air pollution (PM incl. UFP) by a unique translational approach using experimental and computational models in clinical, interventional, and epidemiological studies. A primary goal is to identify disease-relevant biomarkers and understand the molecular pathways of cerebral, pulmonary and cardiovascular NCDs, also by effective translation of animal findings to human health. Our “bench to life” approach on brain-heart axis is entirely driven by profound preclinical mechanistic knowledge and will use novel Multiomics methodology (e.g. redox/phospho-proteomics, “spatial” epigenetics) allowing analysis of key pathomechanisms, to be included in exposure-response models. This will improve risk assessment and allow evaluation of the effectiveness of mitigation strategies. We will also consider the societal circumstances and policies at the national level and their impact on different stakeholders. MARKOPOLO will advance our understanding of the complex interplay between noise, air pollution, and human well-being and provide clearer information and guidelines for various stakeholders.