Bovine atypical interstitial pneumonia (AIP) is a multifaceted disease with several known causes or clinical presentations. Multiple causal agents and management practices have been associated with development of the condition. The sporadic incidence and development of disease in a variety of circumstances argues against a common infectious agent, although cases of AIP are often complicated with bacterial, viral, or mycoplasmal organisms. Lesions develop and progress as a basic response of the lung to injury. Metabolic activation of naturally occurring xenobiotic compounds such as 3-methyl indole, perilla ketone, and 4-ipomeanol produce a clinical syndrome that is indistinguishable from naturally occurring AIP. Pulmonary injury is mediated by formation and activation of intermediate electrophilic compounds that covalently bind to cellular proteins and nucleic acids and ultimately cause cell death. Clara cells (nonciliated bronchiolar) and type I alveolar epithelial cells are primarily responsible for metabolism and activation of these naturally occurring xenobiotics.