This review discusses the long-term efficacy and tolerability of PCSK9-targeted therapy, a novel approach to lowering low-density lipoprotein cholesterol (LDL-C) and reducing the risk of atherosclerotic cardiovascular disease (ASCVD). PCSK9-targeted therapy, including monoclonal antibodies (mAbs) such as evolocumab and alirocumab, and the synthetic small interfering RNA (siRNA) inclisiran, has been shown to effectively lower LDL-C levels and reduce ASCVD risk. The review highlights the balanced adverse event profile, positive effects on plaque burden, and user-friendly formulations of PCSK9-targeted therapy, which offer promise for wider accessibility in the global fight against ASCVD. Key points include the effectiveness and safety of PCSK9-targeted therapy in reducing LDL-C levels, the positive impact on atherosclerotic plaque burden, and the anticipated user-friendly formulations that could enhance treatment adherence. The review also addresses the safety and tolerability of PCSK9-targeted therapy, noting that typical side effects are generally mild and do not significantly impact liver function or muscle enzymes. Additionally, the review discusses the potential effects of PCSK9-targeted therapy on diabetes mellitus, neurocognitive events, and vitamin E levels, concluding that it is unlikely to cause clinically significant impacts on these areas. Overall, PCSK9-targeted therapy is effective and well-tolerated, with high adherence rates, making it a valuable option for high-risk patients with ASCVD.This review discusses the long-term efficacy and tolerability of PCSK9-targeted therapy, a novel approach to lowering low-density lipoprotein cholesterol (LDL-C) and reducing the risk of atherosclerotic cardiovascular disease (ASCVD). PCSK9-targeted therapy, including monoclonal antibodies (mAbs) such as evolocumab and alirocumab, and the synthetic small interfering RNA (siRNA) inclisiran, has been shown to effectively lower LDL-C levels and reduce ASCVD risk. The review highlights the balanced adverse event profile, positive effects on plaque burden, and user-friendly formulations of PCSK9-targeted therapy, which offer promise for wider accessibility in the global fight against ASCVD. Key points include the effectiveness and safety of PCSK9-targeted therapy in reducing LDL-C levels, the positive impact on atherosclerotic plaque burden, and the anticipated user-friendly formulations that could enhance treatment adherence. The review also addresses the safety and tolerability of PCSK9-targeted therapy, noting that typical side effects are generally mild and do not significantly impact liver function or muscle enzymes. Additionally, the review discusses the potential effects of PCSK9-targeted therapy on diabetes mellitus, neurocognitive events, and vitamin E levels, concluding that it is unlikely to cause clinically significant impacts on these areas. Overall, PCSK9-targeted therapy is effective and well-tolerated, with high adherence rates, making it a valuable option for high-risk patients with ASCVD.