Chronic non-communicable diseases (NCDs) account for 2/3 of global deaths annually, primarily due to an aging population and external risk factors such as air/water/soil pollution, traffic noise, mental stress, and climate change emanating from the environment. These factors contribute to premature deaths and loss of healthy life years, as reflected by disability-adjusted life years. The exposome concept was proposed 16 years ago as a new research field to investigate environment-health associations, also by considering the underlying pathophysiological pathways. The exposome describes lifelong environmental exposures, besides pollutants also socioeconomic and lifestyle factors, aiming to explain the associated diseases and deaths. The exposome can be divided into the specific and general external environment and further subcategories such as organ-specific exposomes as well as spatially and temporally restricted pollutomes. The exposome also shows considerable interaction with genetic predisposition and pre-established chronic diseases, characteristics of the vulnerable groups. The present overview provides background information on the impact of the environment on health and disease by considering recent data of the Global Burden of Disease Study. We also explain the exposome concept with the help of selected studies, briefly describe how the exposome is measured, and discuss biomarkers identified by exposomic research and their impact on the development and progression of atherosclerosis. Major pathophysiological pathways comprise exacerbated stress hormone signaling, oxidative stress, inflammation and circadian rhythm dysregulation promoting impairment of cardiometabolic function. The present overview highlights the relevance of the exposome for future health research and preventive medicine, especially concerning cardiovascular diseases and therapy.