Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, encompassing a spectrum of disorders including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Despite significant progress in understanding ALD over the past 20 years, the pathogenesis remains unclear, and no FDA-approved drugs exist for its treatment. This review discusses new insights into ALD pathogenesis and therapeutic targets, utilizing multiomics and other cutting-edge approaches. It also covers preclinical models, the interplay of ALD with metabolic dysfunction, alcohol-associated liver cancer, ALD heterogeneity, and translational research prospects. ALD is characterized by liver injury, including hepatocyte death, inflammation, and fibrosis. Key mechanisms include alcohol metabolism-induced endoplasmic reticulum stress, oxidative stress, and proinflammatory cytokines. Inflammation plays a critical role in ALD progression, with macrophages and neutrophils contributing to liver injury. Gut dysfunction and dysbiosis also contribute to ALD, with alcohol-induced intestinal immune dysfunction and bacterial translocation playing a role. Targeting the gut microbiome, such as through fecal microbiota transplantation, is an area of active research. Mitochondrial dysfunction is another key aspect of ALD, with impaired mitochondrial biogenesis and oxidative stress contributing to hepatocyte death. The heterogeneity of ALD, influenced by genetic factors, drinking patterns, and metabolic dysfunction, complicates treatment. Genetic polymorphisms, such as those in PNPLA3 and TM6SF2, are associated with increased risk of ALD and its progression. Differences in alcohol metabolism between Eastern and Western populations, including ALDH2 and ADH polymorphisms, may affect ALD development and progression. Sex disparities in ALD are also notable, with women being more susceptible to ALD than men with similar alcohol intake. Translational research prospects include the development of biomarkers for early diagnosis and the use of advanced technologies like single-cell and spatial transcriptomics to better understand ALD pathogenesis. Preclinical models and clinical trials are essential for identifying effective therapies for ALD. Despite these advances, no FDA-approved drugs exist for ALD, highlighting the need for further research and development of novel therapeutic strategies.Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, encompassing a spectrum of disorders including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Despite significant progress in understanding ALD over the past 20 years, the pathogenesis remains unclear, and no FDA-approved drugs exist for its treatment. This review discusses new insights into ALD pathogenesis and therapeutic targets, utilizing multiomics and other cutting-edge approaches. It also covers preclinical models, the interplay of ALD with metabolic dysfunction, alcohol-associated liver cancer, ALD heterogeneity, and translational research prospects. ALD is characterized by liver injury, including hepatocyte death, inflammation, and fibrosis. Key mechanisms include alcohol metabolism-induced endoplasmic reticulum stress, oxidative stress, and proinflammatory cytokines. Inflammation plays a critical role in ALD progression, with macrophages and neutrophils contributing to liver injury. Gut dysfunction and dysbiosis also contribute to ALD, with alcohol-induced intestinal immune dysfunction and bacterial translocation playing a role. Targeting the gut microbiome, such as through fecal microbiota transplantation, is an area of active research. Mitochondrial dysfunction is another key aspect of ALD, with impaired mitochondrial biogenesis and oxidative stress contributing to hepatocyte death. The heterogeneity of ALD, influenced by genetic factors, drinking patterns, and metabolic dysfunction, complicates treatment. Genetic polymorphisms, such as those in PNPLA3 and TM6SF2, are associated with increased risk of ALD and its progression. Differences in alcohol metabolism between Eastern and Western populations, including ALDH2 and ADH polymorphisms, may affect ALD development and progression. Sex disparities in ALD are also notable, with women being more susceptible to ALD than men with similar alcohol intake. Translational research prospects include the development of biomarkers for early diagnosis and the use of advanced technologies like single-cell and spatial transcriptomics to better understand ALD pathogenesis. Preclinical models and clinical trials are essential for identifying effective therapies for ALD. Despite these advances, no FDA-approved drugs exist for ALD, highlighting the need for further research and development of novel therapeutic strategies.