AIMS: Our comprehensive review highlights the drug development and pharmacogenomics leading to the recent approval of PCSK9 inhibitors. We also review the anticipated future advances into the uses of PCSK9 inhibition. BACKGROUND: Despite the present advances in pharmacotherapy, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide. Low density lipoprotein-cholesterol (LDL-C) lowering is the primary target for ASCVD risk reduction, showing demonstrable benefits in mortality. However, 70% of events occur even in the presence of statins. This residual risk may be approached with additional LDL-C reduction. Statin intolerance is a common clinical concern affecting adherence and the benefit with statins. There is also significant variation of individual lipid-lowering. Following rapid development, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have progressed from genetic observations, to mechanistic studies, to closer realization of the goal of CVD risk reduction. This review discusses the science behind PCSK9 inhibition, evidence of trials involving efficacy and safety, and reflections of its present and future role in clinical care, especially in high-risk patients with ASCVD, persons with suboptimal responses to statins and familial hyperlipidemia. Monoclonal antibodies have demonstrated LDL-C lowering of up to 57% as monotherapy and up to 73% when added to statins. Statins have limited efficacy in reduction of LDL-C due to an increased number of LDL-receptors. Elevated lipoprotein (a) levels may also be significantly lowered by PCSK9i. The journey from discovery to PSCK9 target validation took less than five years, and development and approval of therapeutic modalities for PCSK9 inhibitors happened over the next seven. This review highlights the drug development and pharmacogenomics leading to the recent approval of two agents, alirocumab and evolocumab, with a third bococizumab, and other novel approaches to the pathway pending. DATA SYNTHESIS: We searched MEDLINE database via Pubmed for reviews, research publications and relevant trials available on PCSK9 inhibition. CONCLUSION: Despite decades of medical advances, ASCVD remains one of the major causes of morbidity and mortality worldwide. Statin use has multiplied since the validation of LDL hypothesis, however, it is undeniable a more effective and well-tolerated agent is needed in significant number or patients. With the arrival of the era of unprecedented CV protection with PCSK9 inhibition, this exciting new therapy holds a pivotal promise as the future of lipid management. The data available already indicate safety, tolerability and superb efficacy of these agents, which are already changing contemporary cholesterol management. The rapid translation of innovative basic science research into drug development may lead to CV outcomes reduction and confirm that this pathway will become prominently utilized.