More than one-third of all deaths in the United States are caused by heart attacks. The disease begins early in life when cholesterol-carrying lipoproteins from the bloodstream enter the lining of the artery and initiate an inflammatory process that leads over many years to a blood clot that stops the circulation. Why does blood contain lipoprotein levels that are high enough to trigger this inflammatory process? This lecture reviews the 33-year journey that Dr. Joseph Goldstein and Dr. Michael Brown took to answer this question, starting at the bedside with a pair of 6- and 8-year-old siblings who had massively elevated blood cholesterol levels and had suffered heart attacks. Their work fostered the development of statins, cholesterol-lowering drugs that are now taken by more than 20 million people worldwide.