Smoking is associated with a lower risk of Parkinson's disease (PD), one of the strongest environmental associations in neuroepidemiology. While the protective effect of smoking on PD is well established, the exact mechanisms remain unclear. Nicotine has been the primary candidate for this protective effect, but clinical trials have failed to show benefits on motor function. Other molecules in smoke, such as carbon monoxide (CO), have shown potential neuroprotective effects in preclinical studies. CO reduces oxidative stress, activates protective pathways, and may contribute to the reduced PD risk among smokers. Additionally, monoamine oxidase-B (MAO-B) inhibitors found in tobacco smoke may also play a role. Other potential mediators include cytochrome P450 enzymes and changes in the gut microbiome. Non-causal explanations, such as reverse causation or shared genetic factors, are also considered. Despite the lack of clear evidence for nicotine's effectiveness, CO shows promise due to its multiple protective mechanisms and safety in clinical trials. Further research is needed to evaluate the disease-modifying potential of other smoke-associated molecules and mechanisms. Smoking's protective effects on PD may lead to new prevention and therapeutic strategies.Smoking is associated with a lower risk of Parkinson's disease (PD), one of the strongest environmental associations in neuroepidemiology. While the protective effect of smoking on PD is well established, the exact mechanisms remain unclear. Nicotine has been the primary candidate for this protective effect, but clinical trials have failed to show benefits on motor function. Other molecules in smoke, such as carbon monoxide (CO), have shown potential neuroprotective effects in preclinical studies. CO reduces oxidative stress, activates protective pathways, and may contribute to the reduced PD risk among smokers. Additionally, monoamine oxidase-B (MAO-B) inhibitors found in tobacco smoke may also play a role. Other potential mediators include cytochrome P450 enzymes and changes in the gut microbiome. Non-causal explanations, such as reverse causation or shared genetic factors, are also considered. Despite the lack of clear evidence for nicotine's effectiveness, CO shows promise due to its multiple protective mechanisms and safety in clinical trials. Further research is needed to evaluate the disease-modifying potential of other smoke-associated molecules and mechanisms. Smoking's protective effects on PD may lead to new prevention and therapeutic strategies.