Hepatitis C virus (HCV) replication is associated with the endoplasmic reticulum (ER), where the virus causes stress. Cells cope with ER stress by activating an adaptive program called the unfolded protein response (UPR), which alleviates this stress by stimulating protein folding and degradation in the ER and down-regulating overall protein synthesis. Recent work suggests that HCV also alters ER calcium homeostasis, inducing oxidative stress. Future progress in understanding the control that HCV exerts over the ER will provide insight into viral strategies for pathogenesis and persistence in chronically infected patients.