The article reviews the advancements in targeting low-density lipoprotein cholesterol (LDL-C) and the need for advanced therapies beyond statins. Statins remain the cornerstone of LDL-C lowering therapy, but their effectiveness is limited by statin intolerance, non-adherence, and heritable lipid disorders. Non-statin therapies, such as ezetimibe, PCSK9 monoclonal antibodies, inclisiran, and bempedoic acid, are discussed, along with their guideline recommendations. For patients with homozygous familial hypercholesterolemia, lomitapide and evinacumab are available. Lipoprotein apheresis remains an effective option for clinical familial hypercholesterolemia and elevated lipoprotein (a). Investigational therapies, including CETP inhibitors, a third-generation PCSK9 inhibitor, and gene editing, are also explored. The article aims to guide physicians on the role of these therapies in achieving appropriate LDL-C goals, providing an algorithm for when to consider each therapy based on efficacy, safety, and outcomes. The need for accurate lab measurements, the safety of very low LDL levels, and the timing of intensification of lipid-modifying strategies are also discussed. The article concludes by highlighting the importance of addressing system failures and disparities in lipid management to improve outcomes for all populations.The article reviews the advancements in targeting low-density lipoprotein cholesterol (LDL-C) and the need for advanced therapies beyond statins. Statins remain the cornerstone of LDL-C lowering therapy, but their effectiveness is limited by statin intolerance, non-adherence, and heritable lipid disorders. Non-statin therapies, such as ezetimibe, PCSK9 monoclonal antibodies, inclisiran, and bempedoic acid, are discussed, along with their guideline recommendations. For patients with homozygous familial hypercholesterolemia, lomitapide and evinacumab are available. Lipoprotein apheresis remains an effective option for clinical familial hypercholesterolemia and elevated lipoprotein (a). Investigational therapies, including CETP inhibitors, a third-generation PCSK9 inhibitor, and gene editing, are also explored. The article aims to guide physicians on the role of these therapies in achieving appropriate LDL-C goals, providing an algorithm for when to consider each therapy based on efficacy, safety, and outcomes. The need for accurate lab measurements, the safety of very low LDL levels, and the timing of intensification of lipid-modifying strategies are also discussed. The article concludes by highlighting the importance of addressing system failures and disparities in lipid management to improve outcomes for all populations.