The tumor microenvironment (TME) has recently been recognized as an important part of tumor development and growth. TME is a dynamic system orchestrated by immune, cancer and inflammatory cells, as well as the stromal tissue and surrounding extracellular matrix. While TME of primary hepatic tumors is usually characterized by a strong inflammatory background, the TME of liver metastases typically consists of otherwise healthy liver tissue. Chronic inflammation and hypoxia are key to the development and progression of primary liver cancer. The injury caused by chronic inflammation creates a condition of immune evasion that initiates a cascade of events that eventually leads to liver carcinogenesis.With liver metastases, primary tumors "prime" the target organs via secreting factors that induce expansion of myeloid cell populations and create a solid ground for successful cancer settlement. Once in the liver, metastatic cells begin a neovascularization process that is driven mainly by VEGF and FGF. Due to high mortality rates associated with liver cancer, as well as the limited effective treatment options for advanced disease, new therapies are urgently needed. Targeting a single molecule in a number of interactions between the tumor and the TME is highly unlikely to reduce tumor growth. Future trials should focus on combination therapies (i.e. targeted therapies combined with immunotherapy) to treat liver malignancies efficiently.