The understanding of the pathobiology of COPD has increased significantly in the last few years. Despite that, prevailing challenges prevent the adequate relief of symptoms, recurrent exacerbations and progression of the disease. A calibrated approach to COPD requires the understanding of the evolution of its early stages (pre-COPD, PRISm), its causes, mimics and phenotypes, and its treatable traits—both pulmonary and extrapulmonary. This chapter also addresses the overlap conditions of COPD (asthma, bronchiectasis, obstructive sleep apnoea, etc) and its comorbidities.