The launch of first-generation protease inhibitors (PIs) was a major step forward in hepatitis C virus (HCV) treatment. However, this major advance has, up to now, only been applicable to genotype-1 patients. Second-wave and second-generation PIs appear to achieve higher antiviral potency, with pan-genotype activities, fewer side-effects and potential activity against PI-resistant mutation by second-generation PIs, through more convenient daily administration. Other direct-acting antivirals (DAAs) include NS5B inhibitors such as nucleoside/nucleotide inhibitors (NIs) and non-nucleoside inhibitors (NNIs). NIs have similar efficacy across all genotypes and present with the highest barrier to resistance of all DAAs to date. PSI-7977, a pyrimidine nucleotide analogue, also has highly potent antiviral activity across all HCV genotypes. In combination with ribavirin in an interferon-free regimen, it can achieve a 100% sustained viral response (SVR) rate in genotype 2/3 treatment-naïve patients. In association with pegylated interferon and ribavirin (PR), it achieves an SVR of 91% in genotype-1 naïve patients. NNIs in association with PR appear to be less potent, but they may nonetheless play a key role in many of the combination trials including either PIs or NIs. NS5A inhibitors also exhibit highly potent antiviral activity. Evaluation of their activity in combination with PIs demonstrated for the first time that an interferon-free regimen can cure genotype-1b null-responder patients. Furthermore, quadruple therapy with PR can achieve a 100% SVR in genotype-1 null-responder patients. Other players in the field, such as cyclophilin inhibitors and therapeutic vaccines, may have a role in combination with DAAs. The near future of HCV treatment looks promising. However, whether or not DAA combinations will lead to an interferon-free regimen for all patients remains an open question.