Ambient air pollution, and especially particulate matter (PM) air pollution <2.5 μm in diameter (PM(2.5)), has clearly emerged as an important yet often overlooked risk factor for atherosclerosis and ischemic heart disease (IHD). In this review, we examine the available evidence demonstrating how acute and chronic PM(2.5) exposure clinically translates into a heightened coronary atherosclerotic burden and an increased risk of acute ischemic coronary events. Moreover, we provide insights into the pathophysiologic mechanisms underlying PM(2.5)-mediated atherosclerosis, focusing on the specific biological mechanism through which PM(2.5) exerts its detrimental effects. Further, we discuss about the possible mechanisms that explain the recent findings reporting a strong association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, increased PM(2.5) exposure, and morbidity and mortality from IHD. We also address the possible mitigation strategies that should be implemented to reduce the impact of PM(2.5) on cardiovascular morbidity and mortality, and underscoring the strong need of clinical trials demonstrating the efficacy of specific interventions (including both PM(2.5) reduction and/or specific drugs) in reducing the incidence of IHD. Finally, we introduce the emerging concept of the exposome, highlighting the close relationship between PM(2.5) and other environmental exposures (i.e.: traffic noise and climate change) in terms of common underlying pathophysiologic mechanisms and possible mitigation strategies.