The neuropeptide somatostatin has been shown to control the secretion of several hormones and growth factors, but also to inhibit the proliferation of several tumor cells. Hepatocellular carcinoma (HCC) is a leading cause of death all over the world due to very limited treatment modalities. Early reports showed that somatostatin may influence HCC growth, making somatostatin a potential therapeutic candidate. The introduction of somatostatin analogues with long half-lives has made this prospect feasible. In this review, experimental data regarding the presence of somatostatin receptors and their functional significance in HCC are presented. Potential mechanisms of direct anti-tumoral activity of somatostatin, including effects on tumor cell proliferation and apoptosis, inhibition of various trophic factors and angiogenesis are also reviewed, as well as indirect actions affecting liver fibrosis, inflammation and macrophage-associated innate immunity. Data on the use of somatostatin analogues for the treatment of induced HCC in experimental animals are presented and human studies of somatostatin treatment of advanced HCC are critically analyzed. Reasons and pitfalls for treatment failures are identified and indications for the proper use of somatostatin, either alone or as an adjunct to other modalities in future trials are proposed