Progress in the discovery of new antiviral medicines is tempered by the rapidity with which drug-resistant variants emerge. A review of the resistance-suppressing properties of four classes of antivirals is presented: influenza virus neuraminidase inhibitors, HIV protease inhibitors, antibodies, and protein-based fusion inhibitors. The analysis supports the hypothesis that the more similar the drug is to the target's natural ligands, the higher the barrier to resistance. However, other factors, such as entropy compensation and solvent anchoring, might also be exploited for improved drug design.