Introduction: Smoking is the main preventable cause of lung cancer. This review summarizes preclinical and clinical data on the mechanisms of smoking-associated cancer development of the major histological lung cancer types small cell lung carcinoma squamous cell carcinoma and pulmonary adenocarcinoma (PAC) and the impact of several factors other than smoking on this process. Areas covered: The role of intracellular signaling induced by nicotinic receptors and beta-adrenergic receptors, the resulting increase in intracellular cyclic adenosine monophosphate (cAMP) as a key driver of PAC and the promoting effects of respiratory tract diseases and their therapeutics, psychological stress and global warming. Expert opinion: Smoking has deleterious effects on the regulation of lung epithelia by neurotransmitter receptors that are further enhanced by gene mutations. Sensitization of the alpha-7 nicotinic receptor (alpha 7nAChR) by COPD enhances the carcinogenic effects of smoking and turns nicotine into a carcinogen. Nicotine vaping may, therefore, cause cancer in individuals with chronic obstructive pulmonary disease. The opposing effects of cAMP on the major lung cancer types indicate that patients with PAC of Clara cell phenotype (PAC-Cl) will benefit from treatment with cAMP reducers and suggest that global warming-induced respiratory tract diseases and their therapeutics cause the global increase in the incidence of PAC.