Nonalcoholic fatty liver disease (NAFLD) is a growing health concern affecting one-third of adults and an increasing number of children in developed countries. The disease begins with the accumulation of triglycerides (TGs) in the liver, which can progress to cirrhosis and liver cancer. While NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood, and therapeutic options are limited. This review discusses recent insights into NAFLD, focusing on human genetic and metabolic studies. Triglycerides emerged early in eukaryotic evolution as a preferred storage nutrient due to their high caloric density and insolubility in water. In humans, hepatic steatosis, the earliest stage of NAFLD, is characterized by the deposition of TGs in hepatocytes. Steatosis can progress to nonalcoholic steatohepatitis (NASH), which is distinguished by hepatocyte injury, inflammation, and fibrosis. NASH can further progress to cirrhosis and liver cancer. The factors promoting TG deposition in the liver and the transition from steatosis to NASH and cirrhosis are not fully understood. Mouse models have provided insights into possible pathological mechanisms, but their relevance to humans is not conclusive. Recent human genetic studies have identified sequence variations associated with NAFLD, offering new molecular clues to its pathogenesis. Hepatic steatosis arises from an imbalance between TG acquisition and removal. Dietary fats, de novo synthesis, and adipose tissue contribute to TG formation. Insulin and glucose promote de novo lipogenesis, while fasting stimulates TG hydrolysis in adipocytes. Studies of rare inherited disorders demonstrate that increased TG content in the liver can cause steatosis. Genetic defects in enzymes involved in TG metabolism, such as ATGL and CGI-58, also lead to steatosis. Obesity and insulin resistance are major risk factors for NAFLD, but other factors, such as gender and ethnicity, also play a role. The heritability of NAFLD is estimated at ~39%, with the *PNPLA3* gene being a consistently associated risk factor. The I148M variant in *PNPLA3* is particularly significant, conferring a higher risk of NAFLD and potentially contributing to disease progression. NAFLD progression to fibrosis and cirrhosis is influenced by factors such as pro-inflammatory cytokines, ER stress, and extrahepatic factors. Longitudinal studies show that a substantial number of individuals with NAFLD improve without treatment, and interventions like bariatric surgery and lifestyle changes can lead to significant improvements. Despite recent advances, many questions remain about the pathogenesis, natural history, and treatment of NAFLD. Further research is needed to understand ethnic differences, the role of *PNPLA3*, and the development of noninvasive methods for early detection and monitoring of NAFLD.Nonalcoholic fatty liver disease (NAFLD) is a growing health concern affecting one-third of adults and an increasing number of children in developed countries. The disease begins with the accumulation of triglycerides (TGs) in the liver, which can progress to cirrhosis and liver cancer. While NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood, and therapeutic options are limited. This review discusses recent insights into NAFLD, focusing on human genetic and metabolic studies. Triglycerides emerged early in eukaryotic evolution as a preferred storage nutrient due to their high caloric density and insolubility in water. In humans, hepatic steatosis, the earliest stage of NAFLD, is characterized by the deposition of TGs in hepatocytes. Steatosis can progress to nonalcoholic steatohepatitis (NASH), which is distinguished by hepatocyte injury, inflammation, and fibrosis. NASH can further progress to cirrhosis and liver cancer. The factors promoting TG deposition in the liver and the transition from steatosis to NASH and cirrhosis are not fully understood. Mouse models have provided insights into possible pathological mechanisms, but their relevance to humans is not conclusive. Recent human genetic studies have identified sequence variations associated with NAFLD, offering new molecular clues to its pathogenesis. Hepatic steatosis arises from an imbalance between TG acquisition and removal. Dietary fats, de novo synthesis, and adipose tissue contribute to TG formation. Insulin and glucose promote de novo lipogenesis, while fasting stimulates TG hydrolysis in adipocytes. Studies of rare inherited disorders demonstrate that increased TG content in the liver can cause steatosis. Genetic defects in enzymes involved in TG metabolism, such as ATGL and CGI-58, also lead to steatosis. Obesity and insulin resistance are major risk factors for NAFLD, but other factors, such as gender and ethnicity, also play a role. The heritability of NAFLD is estimated at ~39%, with the *PNPLA3* gene being a consistently associated risk factor. The I148M variant in *PNPLA3* is particularly significant, conferring a higher risk of NAFLD and potentially contributing to disease progression. NAFLD progression to fibrosis and cirrhosis is influenced by factors such as pro-inflammatory cytokines, ER stress, and extrahepatic factors. Longitudinal studies show that a substantial number of individuals with NAFLD improve without treatment, and interventions like bariatric surgery and lifestyle changes can lead to significant improvements. Despite recent advances, many questions remain about the pathogenesis, natural history, and treatment of NAFLD. Further research is needed to understand ethnic differences, the role of *PNPLA3*, and the development of noninvasive methods for early detection and monitoring of NAFLD.