Modeling acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in animals has proven challenging due to the clinical and pathological complexity of the underlying disease. This has hindered the progress in understanding the cellular and molecular mechanisms that lie beneath AECOPD. In this chapter, we will address modeling possibilities of AECOPD that may be drawn from the current knowledge of factors that cause exacerbations. Importantly, since it is widely accepted that the most common causes of AECOPD are viral and bacterial infections, animal models of AECOPD should incorporate both the causative agents of exacerbation: viruses and bacteria. However, other factors that are also believed to determine both progression of COPD, as well as the frequency and severity of AECOPD, such as proteolytic enzymes, cigarette smoke or other noxious stimuli must also be considered. Such animal models will provide mechanistic insight into the etiology of AECOPD and will prove invaluable in furthering our understanding of key events in disease pathogenesis.