The hydrophobic pocket within viral capsid protein 1 is a target to combat the rhino- and enteroviruses (RV and EV) using small molecules. The highly conserved amino acids lining this pocket enable the development of antivirals with broad-spectrum of activity against numerous RVs and EVs. Inhibitor binding blocks: the attachment of the virion to the host cell membrane, viral uncoating, and/or production of infectious virus particles. Syntheses and biological studies of the most well-known antipicornaviral capsid binders have been reviewed and we propose next steps in this research.