Estrogens are recognized as key players in physiological regulation of various, classical and non-classical, target organs, and tissues, including liver development, homeostasis, and function. On the other hand, multiple, though dispersed, experimental evidence is highly suggestive for the implication of estrogen in development and progression of hepatocellular carcinoma. In this paper, data from our own studies and the current literature are reviewed to help understanding this apparent discrepancy.