Purpose of Review <p>This review summarizes current evidence linking triglyceride-rich lipoproteins (TRLs) to atherosclerotic cardiovascular disease (ASCVD) with emphasis on challenges in translating the epidemiological- and genetic epidemiological findings into therapeutic risk reduction.</p> Recent Findings <p>Elevated triglycerides and TRL-cholesterol are consistently associated with ASCVD risk in both primary- and secondary-prevention populations. Human genetic studies of pathways involving LPL, APOC3, ANGPTL3, and ANGPTL4 strongly support a causal role for TRL metabolism in atherosclerosis. The pathogenic effects of TRLs may differ from those of low-density lipoproteins (LDLs), with TRLs potentially contributing through both cholesterol deposition and activation of inflammatory pathways. However, therapeutic translation has been less straightforward than for LDL. Fibrates have produced inconsistent cardiovascular outcome results, icosapent ethyl reduces cardiovascular events but probably through mechanisms beyond triglyceride lowering alone, and potent APOC3 inhibition has failed to show short-term coronary plaque regression. Together, these findings suggest that TRLs are causal contributors to ASCVD, but that their therapeutic relevance may depend on disease stage, background LDL-C/apoB burden, and residual metabolic risk.</p> Summary <p>TRLs are biologically and genetically linked to ASCVD, but whether lowering TRLs translates into cardiovascular risk reduction may depend on background therapy and cardiovascular risk context. Future trials must determine whether TRL-targeted therapies reduce ASCVD events beyond contemporary prevention, and in which patients this residual risk remains modifiable.</p> Graphical Abstract <p></p>