Patients with familial chylomicronemia (FCS) and severe hypertriglyceridemia (SHTG) suffer from multiple complications, the most severe being acute pancreatitis. Current therapeutic agents, which include fibrates, omega-3 fatty acids, statins, and niacin, are generally ineffective. There are new developments with investigational siRNA therapeutics that silence APOC3, a key regulator of triglycerides and triglyceride-rich lipoproteins. Recent presentations have highlighted outcomes of trials evaluating APOC3 siRNA therapeutics in patients with FCS or SHTG. Drs. Ray, Goldberg, and Ballantyne discuss the findings of these trials, including the PALISADE trial and SHASTA-2 trial with plosaziran, and the potential implications for patients with FCS and SHTG.