This review provides an insight into chronic infection and inflammation-associated hepatocellular carcinoma and potential therapeutic strategies. The inflammatory immune response plays a dual role in cancer development, including hepatocellular carcinoma (HCC). Only chronic and unresolved inflammation induces HCC, which is supported by enormous studies on animal models and clinical analyses. In chronic hepatitis, direct killing of hepatocytes by liver infiltrated lymphocytes and inflammatory cytokines-induced hepatocyte apoptosis and necrosis induce persistent neo-inflammation and hepatocyte generation, which increases the risk of genetic mutation and neoplastic transformation of hepatocytes. Several inflammation-related signaling pathways are involved in hepatocarcinogenesis, including NF-κB, JAK-STAT and MAPK/ERK signaling. In addition, microRNAs (e.g. miR-122, miR124, miR-637, miR-520, and miR-195) also play a key role in HCC development. Therefore, it will be attractive to design therapeutic strategies against HCC by blocking inflammation-inducing factors, targeting pro-inflammatory cytokines and chemokines, and intervening key pathways that orchestrate neo-inflammation networks in HCC development.