The HCV genotype will remain an important, independent pre-treatment predictor of virological response. While direct acting antivirals (DAA) will improve in the coming months the rates of virological response in patients with HCV-1, the development of DAAs effective against other HCV genotypes is at an earlier stage. Therefore, Peg-Interferon and Ribavirin will continue to be used in the near future as standard treatment in these patients. In this manuscript, we will discuss highly debated aspects related to non-1 HCV genotypes. First of all, the predictive role of IL28B genetic variation, secondarily specific aspects related to HCV-4. In the final part, we will highlight potential differences between HCV-2 and HCV-3. Indeed, despite the fact that HCV-2 and HCV-3 have been evaluated together in the majority of studies, HCV-3 patients achieve lower rates of virological response as compared to HCV-2. Whether a genotype individualized treatment may increase virologic response is the object of current investigations.