Bovine respiratory disease (BRD) is the most costly disease of beef cattle in North America. It is multi-factorial, with a variety of physical and physiological stressors combining to predispose cattle to pneumonia. However, efforts to discern which factors are most important have frequently failed to establish definitive answers. Calves are at highest risk shortly after transport. Risk factors include purchasing from sale barns and commingling. It is unclear whether or not these practices increase susceptibility, increase exposure, or are proxies for poor management. Lighter-weight calves appear to be at greater risk, although this has not been consistent. Persistent infection (PI) with bovine virus diarrhea virus increases BRD occurrence, but it is unclear if PI calves affect other cattle in the feedlot. The complexity of BRD has made it difficult to define involvement of individual factors. Stressors may play a role as "necessary but not sufficient" components, requiring additive effects to cause disease.