The occurrence of life-threatening viral infections and the establishment of appropriate defense strategies exhibit major challenges to the disease management in our society. The unpredictable character of viral outbreaks will even be enhanced in the future due to human activities such as increasing international travel, deforestation, changes in social conditions, or influences induced by the climate change. The defense against these pathogenic agents requires preparedness, including successful drug design strategies. Viral proteases represent attractive targets for antiviral therapy because of their essential role in (+)-stranded RNA viruses and retroviruses. In addition, viral proteases can be involved in further processes relevant for viral replication. Numerous efforts have been made to develop potent small-molecule inhibitors of viral proteases; however, until now only a limited number reached the market. In the present contribution, functional aspects of the target proteases, their structural properties, drug design strategies, resulting inhibitors, and resistance management are reviewed and discussed by means of the representative cases of HIV, HCV, SARS coronavirus, and the flaviviruses Dengue and West Nile virus.