Two first-generation non-specific protein 3/4A protease inhibitors (Boceprevir and Telaprevir) have been approved in the U.S. and in Europe in combination with the standard of care for treatment of both previously untreated and prior non responder genotype 1 chronic hepatitis C, based on the results of 5 large phase III trials. With these drugs, futility-stopping rules at weeks 4, 8 and 12 have been provided in order to avoid ineffective therapy and dangerous adverse events. However, despite several guidelines that have been published, a main question remains: how we can identify patients in whom triple therapy will be useless or ineffective? Based on the available data, this review proposes three algorithms to optimize triple antiviral therapy for chronic hepatitis C, to aid physicians avoid prescription of unnecessary treatment, given its substantial side effects and costs.