The worldwide prevalence of cardiovascular disease in general and atherosclerotic coronary artery disease in particular is a health and economic concern of unparalleled proportion. Despite a long history of astute observations beginning in 1575 made by Fallopius, followed by those of von Rokatansky, Virchow, Osler, and Ross, and incremental knowledge of the pathobiology of atherosclerosis to include varying stages of inflammation, response to internally and externally mediated vascular injury, and impaired homeostasis, gaps in the field's understanding persist. Here, we summarize the current scope of the problem for coronary artery disease, emerging constructs in its pathobiology and common clinical phenotypes, potentially useful biomarkers, clinical trials designed specifically to test the 'inflammation hypothesis' of disease, and the interface of pathobiology and precision medicine as a foundation for diagnosis, management, and future advances in the diagnosis, prognosis, natural history, prevention, and optimal management.