The production and secretion of very-low-density lipoproteins (VLDL) by hepatocytes have a significant impact on liver fat content and the concentrations of cholesterol and triglycerides in the circulation, affecting both liver and cardiovascular health. Insulin resistance, excessive caloric intake, and lack of physical activity can lead to overproduction of VLDL, hepatic steatosis, and increased plasma levels of atherogenic lipoproteins. This review focuses on the molecular regulation of VLDL biogenesis, emphasizing the importance of understanding the complex pathways involved in VLDL assembly, trafficking, degradation, and secretion. Recent studies have identified several key players that regulate VLDL metabolism, including RNA-binding proteins, noncoding RNAs, and chaperones. The review highlights the roles of these molecules in maintaining hepatic lipid homeostasis and their potential therapeutic implications for cardiometabolic diseases. Key insights include the involvement of proteins like VIGILIN, TIAL1, HUR, and LZP in VLDL metabolism, as well as the importance of ER-resident proteins such as MTP, DGAT, ACAT, and PEPT in lipidation and synthesis. The review also discusses the role of proteins in the nuclear envelope, such as LAP1 and TORSINA, and the significance of COPII machinery in VLDL transport. Overall, the review provides a comprehensive overview of the latest advancements in the understanding of VLDL biogenesis and secretion, highlighting the need for further research to identify novel therapeutic targets.The production and secretion of very-low-density lipoproteins (VLDL) by hepatocytes have a significant impact on liver fat content and the concentrations of cholesterol and triglycerides in the circulation, affecting both liver and cardiovascular health. Insulin resistance, excessive caloric intake, and lack of physical activity can lead to overproduction of VLDL, hepatic steatosis, and increased plasma levels of atherogenic lipoproteins. This review focuses on the molecular regulation of VLDL biogenesis, emphasizing the importance of understanding the complex pathways involved in VLDL assembly, trafficking, degradation, and secretion. Recent studies have identified several key players that regulate VLDL metabolism, including RNA-binding proteins, noncoding RNAs, and chaperones. The review highlights the roles of these molecules in maintaining hepatic lipid homeostasis and their potential therapeutic implications for cardiometabolic diseases. Key insights include the involvement of proteins like VIGILIN, TIAL1, HUR, and LZP in VLDL metabolism, as well as the importance of ER-resident proteins such as MTP, DGAT, ACAT, and PEPT in lipidation and synthesis. The review also discusses the role of proteins in the nuclear envelope, such as LAP1 and TORSINA, and the significance of COPII machinery in VLDL transport. Overall, the review provides a comprehensive overview of the latest advancements in the understanding of VLDL biogenesis and secretion, highlighting the need for further research to identify novel therapeutic targets.