The article recounts the history of the discovery of the LDL receptor by Joseph L. Goldstein and Michael S. Brown, co-discoverers of the genetic cause of heart attacks and cholesterol metabolism. The discovery introduced three key concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. These concepts are crucial for understanding how statins lower plasma LDL levels, reducing heart attacks and prolonging life. The authors describe their early work on familial hypercholesterolemia (FH), a genetic disorder characterized by high blood cholesterol and early heart attacks. They hypothesized that FH was a defect in regulation rather than enzyme deficiency. Through cell culture studies, they discovered a cell surface receptor for LDL and elucidated the mechanism by which this receptor internalizes LDL particles. They found that FH is caused by genetic defects in the LDL receptor, disrupting normal cholesterol metabolism. The LDL receptor studies also provided evidence for selective uptake of macromolecules into cells, leading to the concept of receptor-mediated endocytosis. The article further discusses the regulation of LDL receptors, the role of feedback mechanisms, and the importance of these discoveries in the development of statins. The latest advancements in understanding cholesterol transport and the functions of NPC1 and NPC2 proteins in lysosomal cholesterol metabolism are also highlighted.The article recounts the history of the discovery of the LDL receptor by Joseph L. Goldstein and Michael S. Brown, co-discoverers of the genetic cause of heart attacks and cholesterol metabolism. The discovery introduced three key concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. These concepts are crucial for understanding how statins lower plasma LDL levels, reducing heart attacks and prolonging life. The authors describe their early work on familial hypercholesterolemia (FH), a genetic disorder characterized by high blood cholesterol and early heart attacks. They hypothesized that FH was a defect in regulation rather than enzyme deficiency. Through cell culture studies, they discovered a cell surface receptor for LDL and elucidated the mechanism by which this receptor internalizes LDL particles. They found that FH is caused by genetic defects in the LDL receptor, disrupting normal cholesterol metabolism. The LDL receptor studies also provided evidence for selective uptake of macromolecules into cells, leading to the concept of receptor-mediated endocytosis. The article further discusses the regulation of LDL receptors, the role of feedback mechanisms, and the importance of these discoveries in the development of statins. The latest advancements in understanding cholesterol transport and the functions of NPC1 and NPC2 proteins in lysosomal cholesterol metabolism are also highlighted.