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The relationship between stress and disease, in particular cardiovascular disease, has long been recognized, whereas the study of the physiological mechanisms that explain this link has only more recently received attention. The acute response to stress is generally thought to be a critically important adaptation designed to activate the system in preparation to cope with the stressor. However, prolonged stimulation of the system (acute and chronic) can lead to deleterious adaptations including the release of inflammatory cytokines (small proteins important in cell signaling) that play a critical role in the development of atherosclerosis. Scientists have therefore used a breadth of protocols and methods to identify the complexity of our fight-or-flight response and demonstrate the synergy between perception, the stress response, physical activity, and health. In addition, the critical assessment of cellular health, the gut microbiome, and genetic polymorphisms have further advanced our understanding of additional therapeutic targets against CVD.