Hepatitis C virus (HCV) infection spreads primarily via contact with infected blood and can establish a persistent infection in 80% of infected individuals, progressively causing chronic liver disease that can lead to hepatocellular carcinoma or end-stage liver disease requiring a transplant. There is no vaccine, and current treatment with interferon and ribavirin is costly, poorly tolerated and ineffective for a large proportion of patients. Technical limitations have stifled the study of HCV immunology, and hence the correlates of resolution remain elusive. HCV robustly infects hepatocytes in the liver, yet HCV RNA is often found to be associated with peripheral blood lymphocytes and extrahepatic manifestations of the disease include B-cell abnormalities. The few existing characterized viral clones that can replicate in vitro have consistently failed to infect immune cells; however, some groups have detected low levels of replication in peripheral blood cells, hinting that occult forms of infection may be possible. HCV lymphotropism remains a controversial subject that needs to be elucidated in order to identify viral reservoirs that may provide targets for therapeutic intervention. The precise interactions between HCV and immune cells need to be determined to establish if the virus has developed mechanisms to modulate immune responses. In the study by Durand et al., correlations were sought between cell tropism and mutations in the 5 noncoding region of the HCV genome, known as the internal ribosome entry site. Key findings are discussed here, highlighting current experimental challenges that surround the topic of HCV lymphotropism.