Respiratory pathogens encounter various lines of defenses before infection of the host is established. The innate immune response represents an important first-line protection mechanism against potentially pathogenic microorganisms during early stages of infection of the naive host. Important players in this host defense system are ‘collectins’, a class of soluble innate immune proteins. Well-characterized members of the collectin family are the surfactant proteins A (SP-A) and D (SP-D). These collectins are expressed in the lung and also in extrapulmonary mucosal tissues. Collectins are secreted as multimers resulting in trimeric clustering of the lectin domains which enables recognition of evolutionary conserved sugar patterns present on the surface of a large variety of pathogens. Binding to collectins may lead to direct agglutination and neutralization of pathogens, to opsonization in order to present bound microbes directly to phagocytes, to modulation of the inflammatory response and to regulation of dendritic cell and T cell functions. In pulmonary tissue, this early acute-phase-like response can be regarded as a crucial layer of protection against a vast array of pathogens that escape the physical barriers and threaten to infect the delicate respiratory epithelium. An important clinical application may be the inhalation, or instillation of collectin-based drugs as part of surfactant therapy, to prevent and treat infectious and inflammatory diseases of newborn infants.