The major targets for direct-acting antivirals (DAAs) are the NS3/4A protease, the NS5A protein, and the NS5B polymerase. The latter enzyme offers several target sites: the catalytic domain for nucleoside/nucleotide analogs and different allosteric sites for non-nucleoside inhibitors. Two protease inhibitors have already been approved and more than 40 new NS3/4A, NS5A, or NS5B inhibitors are in development pipeline. Not only these agents can achieve very high cure rates when combined with PEG-IFN and RBV, but have also started to provide promising results when combined in IFN-free, all-oral combinations. In addition to the more canonical drug targets, new alternative viral targets for small molecule drug development are emerging, such as p7 or NS4B. Current research is focusing on defining the most efficacious DAA combination regimens, i.e., those which provide the highest rates of viral eradication, broadest spectrum of action, minimal or no clinical resistance, shortest treatment duration, and good tolerability.