Chronic obstructive pulmonary disease (COPD) is characterized by poorly reversible airflow limitation associated with airway remodelling and inflammation of both large and small airways. The site of airflow obstruction in COPD is located in the small airways, justifying a focus on this compartment. The structural abnormalities that are found in bronchioles with a diameter less than 2mm are characterized by increased airway wall thickness with peribronchial fibrosis, and by luminal obstruction by mucous exudates. Destruction of alveolar walls, the hallmark of emphysema, may be related to protease-antiprotease imbalance, and to mechanisms involving apoptosis, senescence, and autoimmunity. Cigarette smoke inhalation triggers the recruitment of innate immune cells (neutrophils and macrophages) and putatively adaptive immunity mediated via T and B lymphocytes and lymphoid follicles in the small airways. These data suggest a potential role for therapies that can target remodelling and inflammation in the small airways of patients with COPD.