Chronic obstructive pulmonary disease (COPD) is a common respiratory disease that is characterized by functional and structural alterations primarily caused by long-term inhalation of harmful particles. Cigarette smoke (CS) induces airway inflammation in COPD, which is known to persist even after smoking cessation. This review discusses the basic pathogenesis of COPD, with particular focus on an endogenous protective mechanism against oxidative stress via Nrf2, altered immune response of the airway inflammatory cells, exaggerated cellular senescence of the lung structural cells, and cell death with expanded inflammation. Recently, CS-induced mitochondria autophagy is reported to initiate programmed necrosis (necroptosis). Necroptosis is a new concept of cell death which is driven by a defined molecular pathway along with exaggerated inflammation. This new cell death mechanism is of importance due to its ability to produce more inflammatory substances during the process of epithelial death, contributing to persistent airway inflammation that cannot be explained by apoptosis-derived cell death. Autophagy is an auto-cell component degradation system executed by lysosomes that controls protein and organelle degradation for successful homeostasis. As well as in the process of necroptosis, autophagy is also observed during cellular senescence. Aging of the lungs results in the acquisition of senescence-associated secretory phenotypes (SASP) that are known to secrete inflammatory cytokines, chemokines, growth factors, and matrix metalloproteinases resulting in chronic low-grade inflammation. In future research, we intend to highlight the genetic and epigenetic approaches that can facilitate the understanding of disease susceptibility. The goal of precision medicine is to establish more accurate diagnosis and treatment methods based on the patient-specific pathogenic characteristics. This review provides insights into CS-induced COPD pathogenesis, which contributes to a very complex disease. Investigating the mechanism of developing COPD, along with the availability of the particular inhibitors, will lead to new therapeutic approaches in COPD treatment.