Positron emission tomography (PET) imaging can yield unique mechanistic insights into the pathophysiology of atherosclerosis. ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG), a radiolabeled glucose analog, is retained by cells in proportion to their glycolytic activity. While ¹⁸F-FDG accumulates within several cell types in the arterial wall, its retention correlates with macrophage content, providing an index of arterial inflammation (ArtI) which predicts subsequent cardiovascular disease (CVD) events. Furthermore, ¹⁸F-FDG-PET imaging allows the simultaneous assessment of metabolic activity in several tissues (e.g., brain, bone marrow) and is performed in conjunction with cross-sectional imaging that enables multi-organ structural assessments. Accordingly, ¹⁸F-FDG-PET/computed tomography (CT) imaging facilitates evaluation of disease pathways that span multiple organ systems. Within this paradigm, ¹⁸F-FDG-PET/CT imaging has been implemented to study the mechanism linking chronic stress to CVD. To evaluate this, stress-associated neural activity can be quantified (as metabolic activity of the amygdala (AmygA)), while leukopoietic activity, ArtI, and coronary plaque burden are assessed concurrently. Such simultaneous quantification of tissue structures and activities enables the evaluation of multi-organ pathways with the aid of mediation analysis. Using this approach, multi-system ¹⁸F-FDG-PET/CT imaging studies have demonstrated that chronically heightened stress-associated neurobiological activity promotes leukopoietic activity and systemic inflammation. This in turn fuels more ArtI and greater non-calcified coronary plaque burden, which result in more CVD events. Subsequent studies have revealed that common stressors, such as chronic noise exposure and income disparities, drive the front end of this pathway to increase CVD risk. Hence, multi-tissue multimodality imaging serves as a powerful tool to uncover complex disease mechanisms.