A better knowledge of the mechanisms underlying hepatocellular carcinoma (HCC) growth and spread is essential to improve the available treatment options. So far, the only therapies available for HCC are mainly based on tumor-destructive approaches, whereas no therapies are available to consolidate these invasive therapies or to cure the tumor. The fact that HCC develops on cirrhotic liver strongly limits the use of common anti-cancer drugs, but the need to find new therapies is strongly felt by clinicians. A large body of evidence suggests that the tissue microenvironment represents a potential target for therapies. Consistently, biological therapies such as inhibitors of the epithelial growth factor receptor (EGFR), are currently under investigation. Unfortunately, there is a discrepancy between the very promising experimental data and the results obtained in patients, although limited sample sizes and advanced stage of the disease could be important factors hampering a reliable judgment of the efficacy of such drugs. Nevertheless, a better identification of the molecular pathways involved in drug effectiveness as well as in HCC tumor progression indicates that the tissue microenvironment likely harbors the solution to the problem. In this review the role and the rationale of using biological drugs to target the microenvironment is discussed, taking into consideration new experimental advances in the field.