Antiviral drugs have classically been developed by directly disrupting the functions of viral proteins. However, this strategy has been largely unsuccessful due to the rapid generation of viral escape mutants. It has been well established that as compared to the virus-centric approach, the strategy of developing antiviral drugs by targeting host-dependency factors (HDFs) minimizes drug resistance. However, recent reports have indicated that drug resistance against some of the host-targeting antiviral agents can in fact occur under some circumstances. Long-term selection pressure of a host-targeting antiviral agent may induce the virus to use an alternate cellular factor or alters its affinity towards the target that confers resistance. Alternatively, virus may synchronize its life cycle with the patterns of drug therapy. In addition, virus may subvert host's immune system to perpetuate under the limiting conditions of the targeted cellular factor. This review describes novel potential mechanisms that may account for the acquiring resistance against agents that target HDFs.