BACKGROUND: Respiratory infections result from invasion of the respiratory tract, mainly by viruses, and are the leading cause of acute morbidity in individuals of all ages worldwide. During peak season, picornaviruses cause 82% of all episodes of acute nasopharyngitis (the common cold), the most frequent manifestation of acute respiratory infection, and produce more restriction of activity and physician consultations annually than any other viral or bacterial source of respiratory illness. OBJECTIVE: This article reviews the clinical impact and outcomes of picornavirus-induced respiratory infections in specific populations at risk for complications. It also discusses the potential economic impact of the morbidity associated with picornavirus-induced respiratory infection. METHODS: Relevant literature was identified through searches of MEDLINE, OVID, International Pharmaceutical Abstracts, and Lexis-Nexis. The search terms used were picornavirus, rhinovirus, enterovirus, viral respiratory infection, upper respiratory infection, disease burden, economic, cost, complications, asthma, COPD, immunocompromised, elderly otitis media, and sinusitis. Additional publications were identified from the reference lists of the retrieved articles. CONCLUSIONS: Based on the clinical literature, picornavirus infections are associated with severe morbidity as well as considerable economic and societal costs. Future research should focus on identifying patterns of illness and the costs associated with management of these infections. New treatments should be assessed not only in terms of their ability to produce the desired clinical outcome, but also in terms of their ability to reduce the burden of disease, decrease health care costs, and improve productivity.