Proteins are commonly used as molecular targets against pathogens such as viruses and bacteria. However, pathogens can evolve rapidly permitting their populations to increase in protein diversity over time and thus escape to the activity of a molecular therapy. Subsequently, in order to design more durable and robust therapies as well as to understand viral evolution in a host and subsequent transmission, it is central to understand the evolution of pathogen proteins. This understanding can enable the detection of protein regions that can be potential targets for therapies and predict the emergence of molecular resistance against therapies. In this direction, two articles published recently in the Journal of Molecular Evolution investigated the evolution of proteomes of diverse flaviviruses, including Zika virus, Dengue virus and West Nile virus. Here I discuss the importance of considering the evolution of viral proteins, with the use of as realistic as possible models and methods that mimic protein evolution, to improve the design of antiviral therapies.