Hepatocellular carcinoma is one of the largest causes of cancer-related deaths worldwide for which there are very limited treatment options that are currently effective. The ubiquitin-proteasome system has rapidly become acknowledged as both critical for normal cellular function and a frequent target of de-regulation leading to disease. This review appraises the evidence linking the ubiquitin-proteasome system with this devastatingly intractable cancer and asks whether it may prove to be fertile ground for the development of novel therapeutic interventions against hepatocellular carcinoma.