Targeting COX-2, a key-enzyme of the prostaglandin metabolism, for the treatment of cancer has been in the focus of researchers for about a decade. However, only recently has this topic been related to hepatocellular carcinoma (HCC). HCC is one of the most common cancers and a growing health problem worldwide. At present, only few promising treatment options are available, accentuating the urgent need for novel therapeutic approaches. Since the first report of COX-2 overexpression in HCC, several findings support the notion that selective COX-2 inhibition proves to be beneficial in this malignancy. This review focuses on recent discoveries regarding the pro-tumorigenic potential of COX-2 in HCC and the functional effects of COX-2 inhibition on molecular mechanisms of this malignancy. Of clinical interest, promising data from in vivo experiments and case studies suggest a beneficial effect of COX-2 inhibitors for HCC- therapy. Detailed analysis of COX-2- activated pathways and related mechanisms may enable the evaluation and design of even more specific and combinatorial treatment approaches in the future.