Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging and rapidly growing health problem that currently affects more than one-third of the world general population and more than two-thirds of patients with obesity or type 2 diabetes. MASLD is associated with one or more cardio-metabolic risk factors (CMRFs) that determine the complexity of its natural history and management. Although the term MASLD encompasses a single disease, each CMRF has a different impact on MASLD, and the number of overlapping CMRFs results in a different rate of progression and outcomes of both liver and systemic disease. Its pathogenesis is characterized by insulin resistance, lipotoxicity and a complex cross-talk between liver, adipose tissue, muscle, intestine through the release of hepatokines, cytokines, myokines and inflammatory products. The stage of liver fibrosis is the best predictor of liver outcomes, such as liver failure and mortality, and also predicts the high risk of all-cause mortality associated with the disease. In many cases, the development of hepatocellular carcinoma (HCC) is associated with advanced fibrosis or cirrhosis, although it can occur at all stages of the disease, making prevention difficult. MASLD is characterized by increasing very low-density lipoprotein (VLDL) secretion and chronic low-grade systemic inflammation, which increase the risk of cardio-vascular, renal, and endocrine diseases and extrahepatic cancer. Thus, the management of MASLD requires a holistic approach and treatment of CMRFs through multispecialty collaboration. Currently, diet and physical activity are the effective first-line approaches. There are no approved drugs for the treatment of MASLD, apart from resmetirom, which in a percentage of cases improves metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. We summarize the wide and varied recent literature on the complex etiopathogenetic, clinical and therapeutic aspects of MASLD, connecting and interpreting it to facilitate clinical and management approaches.