For each risk factor for Black Death he discovered, John Graunt in 1662 made a recommendation for action, such as fleeing the night air brought to the City of London docks on foreign ships. These stopped the plague for 200 years! In this honored guest lecture, I focus on thinking beyond the risk factors to their neutralization by effective action without waiting for perfect knowledge of mechanisms. For example, the decreasing risk of repairing atrioventricular septal defect resulted from risk factors that stimulated focused research to devise a better operation. General reduction in risk reduced mortality of aortic valve replacement in patients with chronic aortic regurgitation and severe left ventricular dysfunction. Optimal timing of surgery after stabilizing patients reduced risk of the Norwood procedure. Managing intractable cardiogenic shock reduced risk-adjusted mortality in post-infarct ventricular septal defect. However, we must think beyond traditional risk factors to neutralization of those brought by patient characteristics, imponderables, treatment delivery systems, institutions delivering care to groups of patients, and society caring for its population. There are limitations to thinking beyond risk factors. First, neutralizing strategies require improving processes or introducing new ones. Yet there may be process-outcome disconnect, or even counterintuitive or contradictory relations among outcomes and what are thought to be best processes. Nevertheless, thinking beyond risk factors to their neutralization by research, innovation, and application of knowledge can be as spectacularly successful as was fleeing foul air in halting Black Death.