Acute upper viral respiratory infection (VRI) is the number one cause of illness for which patients seek medical care in the United States. Rhinoviruses, members of the family Picornaviridae, are the causative pathogens in more than half of VRIs, and they are associated with acute exacerbations of respiratory disease, including asthma, sinusitis, otitis media, and COPD. Owing to the lack of commercial availability of rapid and cost-effective laboratory tests to confirm the presence of VRI, the diagnosis is most commonly made empirically, based on patient history and physical examination. Currently, no antiviral agents that are active against picornaviruses are available for clinical use. Antimicrobial agents, frequently prescribed for VRIs, are not active against viruses, and their inappropriate and widespread use has contributed to an increase in antimicrobial resistance among bacteria commonly involved in respiratory tract infections. Several newer antiviral agents are being evaluated for treatment of VRIs. Although a variety of mechanisms and agents have been tested, few have shown significant clinical benefit in human trials. The most advanced antiviral agent in clinical trials is pleconaril, a novel viral capsid–binding inhibitor with potent and highly specific in vitro activity against the majority of serotypes of rhinoviruses and enteroviruses. Clinical trials of pleconaril for the treatment of VRIs have been conducted, and the role of pleconaril in patients with chronic lung disease is being evaluated.