Hepatocellular carcinoma is one of the most prevalent malignancies worldwide and its incidence is increasing. Multimodal strategies directed towards this carcinoma include primary (e.g. immunisation) and secondary (e.g. antiviral therapy) prevention, surgical approaches, novel specific systemic therapies (targeted therapy), and the treatment of comorbidity (cirrhosis). New molecular approaches are currently under development. These tackle several specific targets, with pathology being challenged in many aspects: experimental evaluation, the development of valid tumor-relevant diagnostic tests as well as morphological evaluation in the context of clinical studies, and finally in routine diagnosis.