Hepatocellular carcinoma and cholangiocarcinoma constitute the majority of primary malignant tumors located in the liver, with hepatocellular carcinoma accounting for approximately 80% of these tumors and cholangiocarcinoma representing the remaining 20%. Both are aggressive malignancies, heterogeneous in terms of biological activities and clinical behavior, with dismal outcomes and an increasing incidence worldwide. Radical surgical resection remains the gold standard to date, as adjuvant therapeutic modalities have failed to show a consistent and adequate curative response. However, radical surgical resection is not feasible in most of the patients with such tumors, as tumor size or functional status of the parenchyma does not permit extended hepatic resection. In addition, patients who undergo curative resection often have a high rate of relapse. Multimodal therapeutic approaches, such as the combination of invasive methods (surgical resection, radiofrequency ablation, and two-step or three-step procedures with intermittent portal vein embolization) with interferon-α, systemic chemotherapy, or transarterial catheter embolization, may prolong survival in some patients, but have, however, failed to demonstrate satisfactory results. Therefore, an obvious need emerges for the discovery of new biomarkers to understand the events leading to hepatocarcinogenesis, to relate different phenotypes with differences in clinical behavior and prognosis, and, if possible, to predict response rates to adjuvant therapeutic modalities or, furthermore, to establish novel mechanism-based treatments for hepatic tumors.