Nuclear receptors are key regulators of many cellular functions including energy supply by the direct control of the expression of target genes. They constitute a super-family of transcription factors activated by ligands, hormones or metabolites, and therefore, sensible to host metabolic stimuli. Viral replication and production requires energy and elementary building blocks from the infected cells. Hepatitis B and C virus replication is modulated in part by liver nuclear receptors that regulate the glucose and lipid metabolism. However, nuclear receptors control the two viruses’ replication by different mechanisms. The expression of hepatitis B virus genes is directly under the control of nuclear receptors, which bind to the viral genome regulatory regions. Viral replication and production may, therefore, be optimal when cells receive the correct metabolic signals. Hepatitis C virus replication and production depend to a large extent on lipidogenesis and lipoprotein secretion. The role of nuclear receptors in controlling hepatitis C replication may be to turn on the cellular mode that would provide the appropriate metabolic environment for viral replication.