Recent studies focusing on Hepatitis C virus (HCV) survival strategies revealed that viral proteins may interfere with pathways of retinoid-acid-inducible gene I and Toll-like receptor 3, which constitute two major pathways of host defense triggered by viral nucleic acids. In particular, HCV seems to interfere at several different points with interferon (IFN) and IFN-stimulated gene signaling. A powerful strategy employed by the virus is genetic variability resulting in the constant and dynamic development of variants capable of avoiding eradication by host defenses. Several studies have reported that transmission of infection may be limited to a few variants present within the quasispecies population. Thus, viral populations found in children infected at birth were found to be more homogeneous than those in mothers. HCV infection is common among HIV-positive patients, as the two pathogens share similar routes of transmission. HCV is a positive-strand RNA virus, which replicates through negative-strand RNA, the presence of which could be regarded as direct evidence of ongoing replication. HCV RNA-negative strand was detected only in a minority of cases; however, it is likely that the strand-specific assays are not sensitive enough to detect low-level extra hepatic replication. Infected macrophages and microglia cells could release proinflammatory cytokines, such as tumor necrosis factor (TNF)- α, interleukin-1 (IL-1), and IL-6, neurotoxins such as nitric oxide, and viral proteins, which could induce alteration in brain function leading in turn to neurocognitive dysfunction and depression.