Current estimates indicate that the hepatitis C virus is the leading cause of death in the United States with infection rates steadily increasing. Successful treatment is made difficult by the presence of various host, virus, and treatment-related factors, warranting the development of new approaches to combat the silent epidemic. The addition of telaprevir and boceprevir to the pharmacotherapeutic arsenal drastically improved success rates in genotype 1 infected patients, but rapid development of resistance mechanisms, increases in adverse effects, and a low spectrum activity proved to be barriers to efficacious treatment. In late 2013, two new agents were approved – sofosbuvir and simeprevir – that have higher barriers to resistance, favorable safety profiles, and profoundly improved success rates; however higher costs associated with the new medications could limit their wider utilization. Further strategies to combat the virus are under development, ranging from interferon-free regimens as well as prophylactic and therapeutic vaccines to applications of nanotechnology, helping us get closer to improved treatment of patients infected with hepatitis C.