IntroductionThe two cysteine proteases from the coronaviruses, which produced deadly outbreaks in the last two decades, SARS CoV-1/2, and MERS, the main protease (M-pro) and the papain-like protease (PLP) are conserved among the three pathogens and started to be considered as exciting drug targets for developing antivirals.Areas coveredWe review the drug design landscape in the scientific and patent literature to design peptidomimetic and non-peptidomimetic protease inhibitors (PIs) targeting these proteins.Expert opinionThe X-ray crystal structures of some of these proteases, alone and in complex with various inhibitors, were crucial for the discovery of effective such compounds, some of which also showed considerable antiviral activity and are considered preclinical candidates to fight these emerging infections, which in the case of Covid-19 already provoked an unprecedented worldwide pandemic.