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Exposure to cigarette smoking is extensive in rural Appalachia where one in four adults’ smokes. The clinical implications of this habit are evident among patients with some of the highest national rates for chronic obstructive pulmonary disease (COPD), lung cancer, and pulmonary fibrosis. Individuals undergoing surgical lung resection for suspicious lung nodules or masses at a major rural academic center in the area demonstrated an excessive burden of histologic emphysema (73.5%). This destructive process of the alveoli was linked to a significant burden of comorbid conditions, various radiologic patterns of interstitial lung diseases and interstitial lung abnormalities, histologic fibrosis, inflammatory processes (respiratory bronchitis, desquamative interstitial pneumonia, peribronchiolar metaplasia), anthracosis, and lung cancer. Physiologically, this combination of injuries imposed substantial limitations. Findings presented may enhance the understanding of concurrent changes occurring in the smoker. The complex inter-relationships and disparities between clinical COPD, radiologic and histologic emphysema are defined. While emphysema remains an irreversible pathology, associated inflammatory and fibrotic conditions are possibly amenable to earlier smoking cessation strategies and available disease-modifying therapies.