Chronic infections with Hepatitis C (HCV) and Hepatitis B (HBV) viruses (which infect 170 and 350 million persons in the world, respectively) lead to development of cirrhosis and are responsible for 80% of hepatocellular carcinoma cases worldwide. A preventive vaccine exists for HBV (a small, enveloped DNA Hepadnavirus), but not for HCV (enveloped virus with ssRNA genome; 6 main genotypes; Flaviviridae family). A striking progress in therapeutic treatments against HCV has been achieved, which is based on the use of direct antiviral agents (DAA) in association or not with ribavirin and pegylated interferon a (PEG-IFN). Treatment of HBV-infected patients (PEG-IFN + nucleos(t)ides analogs) still remains problematic. We investigate the interactions of HCV and HBV with their target cell in view of development of new approaches to block cell entry, inhibit their replication, propagation and persistence. We analyze the interactions of HCV with components of the Interferon and inflammation pathways and the mechanisms involved in HCV cell entry and its intracellular transport. We investigate the cellular effectors involved in HBV replication and pathogenesis.