The modern history of cholesterol-lowering drugs began in 1972 with the discovery of compactin, an active compound that inhibited cholesterol biosynthesis. Since 1987, statins have been the cornerstone for treating atherosclerotic cardiovascular disease (ASCVD). Ezetimibe, the first agent inhibiting intestinal cholesterol absorption, was approved in 2002. The discovery of gain-of-function PCSK9 genetic mutations in 2015 opened a new era in lipid-lowering therapies, leading to the development of monoclonal antibodies and small-interfering RNA (siRNA) approaches. Bempedoic acid, an oral adenosine triphosphate citrate lyase inhibitor, was recently approved for reducing major adverse cardiovascular events in both primary and secondary prevention. This narrative review summarizes the pharmacological properties and clinical efficacy of these agents used for tailored therapy of hypercholesterolemia in patients with ASCVD. Statins, the most widely used drugs, reduce LDL-C by 20–60% and are well-tolerated, although some patients may experience muscle complications. Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, reduces LDL-C by 20–25% in monotherapy. Monoclonal antibodies blocking PCSK9 action, such as alirocumab and evolocumab, produce a sustained reduction of LDL-C by approximately 55%. Inclisiran, a siRNA therapy targeting hepatic PCSK9 mRNA, achieves a long-term reduction of LDL-C by 50%. Bempedoic acid, an oral cholesterol synthesis inhibitor, reduces LDL-C by 20–25% and is particularly effective when combined with ezetimibe. These agents offer a range of options for managing hypercholesterolemia and reducing cardiovascular risk.The modern history of cholesterol-lowering drugs began in 1972 with the discovery of compactin, an active compound that inhibited cholesterol biosynthesis. Since 1987, statins have been the cornerstone for treating atherosclerotic cardiovascular disease (ASCVD). Ezetimibe, the first agent inhibiting intestinal cholesterol absorption, was approved in 2002. The discovery of gain-of-function PCSK9 genetic mutations in 2015 opened a new era in lipid-lowering therapies, leading to the development of monoclonal antibodies and small-interfering RNA (siRNA) approaches. Bempedoic acid, an oral adenosine triphosphate citrate lyase inhibitor, was recently approved for reducing major adverse cardiovascular events in both primary and secondary prevention. This narrative review summarizes the pharmacological properties and clinical efficacy of these agents used for tailored therapy of hypercholesterolemia in patients with ASCVD. Statins, the most widely used drugs, reduce LDL-C by 20–60% and are well-tolerated, although some patients may experience muscle complications. Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, reduces LDL-C by 20–25% in monotherapy. Monoclonal antibodies blocking PCSK9 action, such as alirocumab and evolocumab, produce a sustained reduction of LDL-C by approximately 55%. Inclisiran, a siRNA therapy targeting hepatic PCSK9 mRNA, achieves a long-term reduction of LDL-C by 50%. Bempedoic acid, an oral cholesterol synthesis inhibitor, reduces LDL-C by 20–25% and is particularly effective when combined with ezetimibe. These agents offer a range of options for managing hypercholesterolemia and reducing cardiovascular risk.