Hepatocellular carcinoma (HCC) is the commonest primary liver cancer and the second leading cause of cancer death worldwide. Obesity is rapidly becoming pandemic and associated with increased carcinogenesis. In this review, we describe the obesity-related factors that influence the development of HCC. We provide evidence of strong links between neural regulation, endocrine and HCC in obesity. We discuss recent advances in our understanding of how adipose tissue alters hepatic metabolism and immune response in HCC development through inter-organ communication. Taken together, our review aims to provides a concise and up-to date summary about the connection between obesity and HCC, with emphasis on the opportunities for effective strategies in preventing the development of HCC in obese individuals.