Animal models of disease help accelerate the translation of basic science discoveries to the bedside, because they permit experimental interrogation of mechanisms at relatively high throughput, while accounting for the complexity of an intact organism. From the groundbreaking observation of emphysema-like alveolar destruction after direct instillation of elastase in the lungs to the more clinically relevant model of airspace enlargement induced by chronic exposure to cigarette smoke, animal models have advanced our understanding of alpha-1 antitrypsin (AAT) function. Experimental in vivo models that, at least in part, replicate clinical human phenotypes facilitate the translation of mechanistic findings into individuals with chronic obstructive pulmonary disease and with AAT deficiency. In addition, unexpected findings of alveolar enlargement in various transgenic mice have led to novel hypotheses of emphysema development. Previous challenges in manipulating the AAT genes in mice can now be overcome with new transgenic approaches that will likely advance our understanding of functions of this essential, lung-protective serine protease inhibitor (serpin).