Elastase and chronic cigarette smoke exposure animal models are commonly used to study lung morphologic and functional changes associated with emphysema-like airspace enlargement in various animal species. This chapter describes the rationale for using these two models to study mechanisms of COPD pathogenesis and provides protocols for their implementation. E-cigarettes are an emerging health concern and may also contribute to lung disease. Accordingly, approaches to study e-cigarette vapors are provided. This chapter also includes methods and tools necessary to assess lung morphologic and functional changes in animals with emphysema-like airspace enlargement.