Low-density lipoprotein cholesterol (LDL-C)-lowering therapy that increases LDL receptor expression in several ways robustly reduces the risk of atherosclerotic cardiovascular disease (CVD). However, a substantial risk of CVD still remains after intensive LDL-C reduction, which requires new treatment modalities for dyslipidemia and cardiovascular risk management. Triglycerides (TGs) and triglyceride-rich lipoproteins (TRLs) have received attention as indicators of residual cardiovascular risk and as direct causal factors for atherosclerosis and CVDs. Advances in understanding TG and TRL metabolism and their association with clinically evident CVDs have led to the development of novel therapeutic targets, including apolipoprotein C-III (apoC-III) and angiopoietin-like protein 3 (ANGPTL3). Genetic association studies have indicated that both apoC-III and ANGPTL3 play a causal role in the development of atherosclerotic CVD. Both molecules contribute to lipid dysregulation and atherosclerosis primarily by inhibiting lipoprotein lipase; however, recent evidence has shown that novel pathways exist in relation to their lipid-modifying activities. Notably, recent progress in therapeutic approaches, such as monoclonal antibodies or antisense oligonucleotides, has led to several novel therapeutics targeting apoC-III and ANGPTL3. This review summarized the recent updates and discussions related to apoC-III and ANGPTL3 expression.