Acute asthma exacerbations in adults and children are triggered commonly by viral upper respiratory infections. The main culprits are respiratory syncytial virus and parainfluenza virus in young children and rhinovirus in older children and adults. Recent investigations in multiple laboratories have increased our understanding of the nature of this relationship. Postulated mechanisms include a viral modulation of airway epithelial and inflammatory cell function with the release of proinflammatory cytokines and mediators, airway microvascular endothelial cell function leading to airway wall edema, airway smooth muscle cell functions, and neural regulation of airway tone via either enhanced parasympathetic efferent neuronal activity, activation of the release of bronchoactive neuropeptides from sensory c-fibers in the airways, or modulation of the influence of the nonadrenergic/noncholinergic neuronal system on airway tone. There also is evidence that rhinoviruses may directly infect the lower airways. These potential mechanisms likely relate to, are superimposed on, and potentiate preexisting inflammatory and immune responses that are characteristic of the atopic asthmatic airway. Undoubtedly, future efforts will be aimed at the prevention of asthma exacerbations via well-targeted and well-conceived strategies for prevention and/or treatment of upper respiratory infections.