Purpose of Review <p>Apolipoprotein C-III (apoC-III) is a central regulator of triglyceride metabolism. Elevated triglyceride levels are associated with increased risk of acute pancreatitis and atherosclerotic cardiovascular disease (ASCVD).</p> Recent Findings <p>Conventional triglyceride-lowering therapies, such as fibrates and omega-3 fatty acids, have limited efficacy in reducing triglycerides and in reducing the risk of pancreatitis or ASCVD in patients with severe hypertriglyceridemia. ApoC-III inhibits lipoprotein lipase and impairs clearance of both triglyceride-rich and cholesterol-rich lipoproteins. Novel therapies targeting <i>APOC3</i> mRNA to reduce triglycerides, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), achieve greater triglyceride reductions than standard agents. Volanesorsen and olezarsen, both ASOs, are approved as an adjunct to diet to reduce triglycerides in familial chylomicronemia syndrome (FCS) in different regions. Plozasiran, an siRNA, is in late-stage clinical development. Indirect cross-trial comparisons were performed, aligned by timepoint and outcome measures, and indicate comparable efficacy of olezarsen and plozasiran in patients with chylomicronemia.</p> Summary <p><i>APOC3</i> inhibition is now an established therapeutic approach for reducing the risk of acute pancreatitis in FCS, with three agents, volanesorsen, olezarsen, and plozasiran, demonstrating efficacy. However, its role in ASCVD prevention remains unproven. This review evaluates current <i>APOC3 </i>– targeted therapies for FCS, including available comparative data, and synthesizes the emerging literature on the potential of <i>APOC3</i> inhibition to reduce the burden of acute pancreatitis in broader populations with severe hypertriglyceridemia, as well as its potential role in ASCVD risk reduction.</p>