Persistent inflammation is known to promote and exacerbate malignancy. Primary liver cancer, mostly hepatocellular carcinoma (HCC), is a clear example of inflammation-related cancer as more than 90 % of HCCs arise in the context of hepatic injury and inflammation. HCC represents the fifth most common malignancy and the third leading cause of cancer-related death worldwide with about one million new cases diagnosed every year with almost an equal number of deaths. Chronic unresolved inflammation is associated with persistent hepatic injury and concurrent regeneration, leading to sequential development of fibrosis, cirrhosis, and eventually HCC. Irrespective of the intrinsic differences among various etiological factors, a common denominator at the origin of HCC is the perpetuation of a wound-healing response activated by parenchymal cell death and the resulting inflammatory cascade. Hence, the identification of fundamental inflammatory signaling pathways causing transition from chronic liver injury to dysplasia and HCC could depict new predictive biomarkers and targets to identify and treat patients with chronic liver inflammation. This chapter critically discusses the roles of several major cytokines, chemokines, growth factors, transcription factors, and enzymes as well as a distinct network of inflammatory signaling pathways in the development and progression of HCC. It also highlights and analyzes preclinical animal studies showing innovative approaches of targeting inflammatory mediators and signaling by a variety of natural compounds and synthetic agents to achieve effective therapy as well as prevention of hepatic malignancy. Additionally, current limitations and potential challenges associated with the inhibition of inflammatory signaling as well as future directions of research to accelerate clinical development of anti-inflammatory agents to prevent and treat liver cancer are presented.