For the minority of patients with hepatocellular carcinoma (HCC), surgical or locally ablative therapies may offer the prospect of cure. However, the majority of patients present with advanced disease, such that treatment with curative intent is no longer possible. For some of these patients, with good hepatic reserve and a patent portal venous system, chemoembolisation may afford a modest survival benefit. The remainder of patients are frequently treated with systemic therapies with palliative intent. However, no drug treatment has yet clearly demonstrated a significant beneficial effect on survival or quality of life. Thus, there is an urgent need for novel approaches. Gene- and immunotherapy approaches using a variety of strategies are in development at present. HCC possesses several characteristics that make it an attractive target for these therapies. This review aims to summarise the approaches to gene- and immunotherapy for HCC, with particular reference to strategies that are entering clinical trials. It will then describe some of the obstacles to the success of these new approaches and provide opinion regarding ongoing and future developments. The challenge remains to design clinical trials to optimally evaluate these agents and allow feedback to the laboratory for their ongoing development.