The liver integrates metabolic outcomes with nutrient intake while preventing harmful signals derived from the gut to spread throughout the body. Direct blood influx from the gastrointestinal tract through the portal vein makes the liver a critical firewall equipped with a broad array of immune cells and innate immune receptors that recognize microbial-derived products, microorganisms, toxins and food antigens that have breached the intestinal barrier. An overwhelming amount of evidence obtained in the last decade indicates that the intestinal microbiota is a key component of a wide variety of physiological processes, and alterations in the delicate balance that represents the intestinal bacterial communities are now considered important determinants of metabolic syndrome and immunopathologies. Moreover, it is now evident that the interaction between the innate immune system and the intestinal microbiota during obesity or autoimmunity promotes chronic liver disease progression and therefore it might lead to novel and individualized therapeutic approaches. In this review, we discuss a growing body of evidence that highlights the central relationship between the immune system, the microbiome, and chronic liver disease initiation and progression.