Recent evidence indicates that the intestinal microflora plays a critical role in physiological and pathological processes; in particular, it is now considered a key determinant of immune pathologies and metabolic syndrome. Receiving the majority of its blood supply from the portal vein, the liver represents the first line of defense against food antigens, toxins, microbial-derived products, and microorganisms. Moreover, the liver is critically positioned to integrate metabolic outcomes with nutrient intake. To accomplish this function, the liver is equipped with a broad array of immune networks. It is now evident that, during pathological processes associated with obesity, alcohol-intake, or autoimmunity, the interaction between these immune cell populations and the intestinal microbiota promotes chronic liver disease progression and therefore they represent a novel therapeutic target. Herein, we highlight recent studies that have shed new light on the relationship between the microbiome, the innate immune system, and chronic liver disease progression.