Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related disease worldwide. Although HCC is mainly associated with viral hepatitis and alcoholic cirrhosis, numerous physiological and biochemical events are associated with HCC progression. The transcription factor Twist, which plays a key role in epithelial to mesenchymal transition, is reported to be associated with HCC. Overexpression of Twist causes various biochemical changes, such as increase of cell proliferation, reduction of apoptosis, cell cycle deregulation, generation of hepatic cancer stem cells, and in some cases, drug resistance. These changes result in various physiological changes, such as angiogenesis, cellular migration and invasion, and vasculogenic mimicry, which ultimately causes hepatocellular metastasis. Interestingly, targeting Twist via different strategies, especially small RNA technology, has shown promising therapeutic potential for future HCC treatment.