Hepatocellular carcinoma is often diagnosed at a late, inoperable stage for which there are no uniformly efficacious treatment available presently. The oral anti-oestrogen drug, tamoxifen, has been used in such patients, based on the belief that the growth of hepatocellular carcinoma is promoted by endogenous oestrogen via a receptor-mediated process. In this review, we examine the trials reported in the literature using tamoxifen in hepatocellular carcinoma. Randomized controlled trials with tamoxifen have so far revealed mixed results. We propose that this may be due to the fact that the mechanism of action of tamoxifen in hepatocellular carcinoma is via an oestrogen-receptor independent pathway that requires much higher doses of tamoxifen for activation than those used in the trials so far. Thus there must be a paradigm shift to dissociate the action of tamoxifen from oestrogen receptors in hepatocellular carcinoma. This means that future trials with tamoxifen in hepatocellular carcinoma should use higher doses of tamoxifen, at least four to eight-fold that of the dose that is efficacious in an oestrogen-receptor dependent mechanism.