The rhinovirus and enterovirus members of the picornavirus family are responsible for the majority of the mild upper respiratory infections most often referred to as the common cold as well as more serious illnesses including myocarditis. Much progress has been made in the identification and development of antiviral agents which specifically target the capsid of the picornaviruses. Preclinical and clinical efficacy data will be discussed on the WIN series of antiviral agents which were the result of a conventional drug discovery approach. The design of new agents is being assisted by the availability of atomic resolution data on the interaction of this class of antiviral agents with the viral capsid.