The production and secretion of very-low-density lipoproteins (VLDL) by hepatocytes significantly impact liver fat content and circulating cholesterol and triglyceride levels, affecting both liver and cardiovascular health. Insulin resistance, excessive caloric intake, and lack of physical activity are linked to increased VLDL production, hepatic steatosis, and elevated levels of atherogenic lipoproteins. VLDL biogenesis and secretion involve approximately 50 molecular entities, with early stages well understood, while later steps remain less clear. VLDL secretion is increased in most people with atherogenic dyslipidemia, and the liver has limited capacity to assemble and secrete VLDL to prevent lipid accumulation. Understanding VLDL biogenesis and secretion is crucial for developing therapeutic strategies to improve cardiovascular and hepatic health. Recent studies have identified new molecular players in VLDL assembly, trafficking, and secretion, including proteins involved in lipidation, ER-associated degradation, and transport. These studies highlight the complex interplay between VLDL and lipid droplet biology, as well as the role of various proteins in regulating VLDL secretion and lipid homeostasis. The review emphasizes the importance of understanding these processes to develop effective treatments for cardiometabolic diseases.The production and secretion of very-low-density lipoproteins (VLDL) by hepatocytes significantly impact liver fat content and circulating cholesterol and triglyceride levels, affecting both liver and cardiovascular health. Insulin resistance, excessive caloric intake, and lack of physical activity are linked to increased VLDL production, hepatic steatosis, and elevated levels of atherogenic lipoproteins. VLDL biogenesis and secretion involve approximately 50 molecular entities, with early stages well understood, while later steps remain less clear. VLDL secretion is increased in most people with atherogenic dyslipidemia, and the liver has limited capacity to assemble and secrete VLDL to prevent lipid accumulation. Understanding VLDL biogenesis and secretion is crucial for developing therapeutic strategies to improve cardiovascular and hepatic health. Recent studies have identified new molecular players in VLDL assembly, trafficking, and secretion, including proteins involved in lipidation, ER-associated degradation, and transport. These studies highlight the complex interplay between VLDL and lipid droplet biology, as well as the role of various proteins in regulating VLDL secretion and lipid homeostasis. The review emphasizes the importance of understanding these processes to develop effective treatments for cardiometabolic diseases.