The liver has multiple functions and is central to most of them. It is the primary energy storage and synthesis source and filters food, senescent cells, and hemoglobin. The biliary system contributes to the digestion and elimination of discarded products, including processed hemoglobin in biliverdin/bilirubin. In addition, the liver is a checkpoint to mount immune responses. As a gatekeeper, the liver plays a central role in controlling the spread of harmful hazards entering the gastrointestinal system, or via hematogenous or lymphatic spread. Given the complex structure of the liver and its interaction with multiple products, it becomes a target of the immune system. Various systemic autoinflammatory diseases may affect the liver with a predilection for selective compartments within the organ and at different severity stages. Unique autoimmune inflammatory hepatopathies should be differentiated from systemic diseases and/or related to comorbid autoimmune diseases, when present. The appropriate diagnosis and association with the systemic autoimmune disease or immune deficiency will contribute to implementing a correct therapeutic approach, either pharmacologic or based on other modalities, such as diet modification. In this chapter, we highlight the primary hepatic inflammation in various presentations and hepatic manifestations within systemic illnesses. We describe the underlying pathogenic mechanism orchestrating each disorder and the current therapeutic approach for each. Additionally, we describe a list of pharmacologic drugs commonly used in rheumatic disease that carry a potential for hepatotoxicity.