In ruminants, respiratory disease is multifactorial and a leading cause of morbidity and mortality. Pulmonary innate immunity is the first line of defense for the respiratory tract. Alteration of regulation, expression, and function of these factors may be important to disease development and resolution. Many antimicrobial peptides and surfactant proteins are constitutively expressed in the respiratory tract and expression levels are regulated. Beta-defensins are cationic peptides with broad antimicrobial activity against bacterial, viral and fungal pathogens. Beta-defensins are primarily expressed in mucosal epithelia (and in some species leukocytes); where they may also participate in chemotaxis, wound repair and adaptive immune responses. Surfactant proteins A and D are secreted pulmonary surfactant proteins that have antimicrobial and immune regulatory activity. Anionic peptide is a constitutively expressed, aspartate-rich peptide that has antimicrobial activity and is most prominent during reparative epithelial hyperplasia. Regulation of these immune defense components by stress, pathogens, and inflammatory cytokines may play a role in the susceptibility to, severity and resolution of respiratory infection. The expression patterns of these molecules can be specific for host-species, class of pathogen and stage of infection. Understanding the regulation of antimicrobial peptide/protein expression will further enhance the potential for novel prophylactic and therapeutic modalities to minimize the impact of respiratory disease.