Hepatocellular carcinoma (HCC) ranks as the second cause of death related to cancer. The main cause for HCC is liver cirrhosis whatever the cause. The highest rates are seen in Asia and Africa due to higher incidence of hepatitis B, though it is increasing in developed countries due to hepatitis C. Unfortunately, most of cases present in an advanced stage having only option of systemic therapy. HCC continues to be a challenge to treatment due to chemoresistance, liver dysfunction which hinders the delivery of the drugs. HCC is poorly chemo sensitive. In the past years, no single treatment have shown to be superior to another treatment. Until recently patients in need for systemic therapy had nothing except tyrosine kinase inhibitors (TKI) as an option for treatment. In the last decade, immunotherapy introduced in many cancers seems promising in HCC since all HCC develop in cirrhotic patients that have an immunosuppressive environment that might be modulated. Although new systemic therapies provide hope for advanced non-respectable HCC cases yet, the adverse effects related to these drugs should be highly anticipated and considered. This chapter will discuss the evolution of systemic therapy for HCC and highlight the adverse effects associated with the use of systemic therapy in HCC management the chapter will discuss causes of inequality in access to HCC systemic and ways to address this inequality.