Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, affecting up to one-fourth of the population. This review explores the molecular mechanisms underlying hepatic steatosis in NAFLD, focusing on four major pathways of lipid homeostasis in the liver: lipid acquisition, de novo lipogenesis (DNL), fatty acid oxidation (FAO), and lipid export. Hepatic steatosis results from an imbalance between lipid acquisition and disposal, with increased uptake and DNL in NAFLD, while FAO and export may initially increase but plateau or decrease as the disease progresses. The review discusses the role of specific proteins and pathways, such as fatty acid transport proteins (FATP), CD36, caveolins, FABP1, SREBP1c, ChREBP, ACC, FASN, PPARα, CYP2E1, and MTTP, in these pathways. It highlights the complex interplay between these pathways and the potential for therapeutic interventions targeting specific components. The review also addresses the challenges in developing effective treatments for NAFLD due to the heterogeneity of the disease and the lack of predictive pre-clinical models.Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, affecting up to one-fourth of the population. This review explores the molecular mechanisms underlying hepatic steatosis in NAFLD, focusing on four major pathways of lipid homeostasis in the liver: lipid acquisition, de novo lipogenesis (DNL), fatty acid oxidation (FAO), and lipid export. Hepatic steatosis results from an imbalance between lipid acquisition and disposal, with increased uptake and DNL in NAFLD, while FAO and export may initially increase but plateau or decrease as the disease progresses. The review discusses the role of specific proteins and pathways, such as fatty acid transport proteins (FATP), CD36, caveolins, FABP1, SREBP1c, ChREBP, ACC, FASN, PPARα, CYP2E1, and MTTP, in these pathways. It highlights the complex interplay between these pathways and the potential for therapeutic interventions targeting specific components. The review also addresses the challenges in developing effective treatments for NAFLD due to the heterogeneity of the disease and the lack of predictive pre-clinical models.