Cigarette smoke has always been the single most preventive cause of death in the world. In 2011, over 460,000 died from cigarette smoke-related diseases in US. The detrimental effects of cigarette smoke on human beings are due to the presence of many carcinogens and other components (e.g. nicotine and tar). Nicotine is now accepted as one of the major components responsible for gastrointestinal disorders. Cigarette smoking, nicotine and a nicotine-derived nitrosamine, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered as risk factors for gastrointestinal cancer, however, the underlying mechanism remains largely unknown. Previous studies reported that cigarette smoke and nicotine aggravated inflammation not only in the stomach, but also in the colon. The carcinogenic actions of cigarette smoke, nicotine and NNK on gastrointestinal cancers development have been widely studied. The strong association of cyclooxygenase-2 (COX-2) with gastrointestinal diseases has been extensively studied, however, due to the unresolved cardiovascular risk, it is of great importance to develop other new anti-cancer drugs for the treatment of cancers. This current review aims to provide an overview of the effects of cigarette smoke, nicotine and NNK on gastrointestinal inflammation, and also the carcinogenic properties in cancer development (tumor growth, angiogenesis and epithelial-mesenchymal transition). In addition, current studies on nicotinic acetylcholine receptors, adrenergic receptors and miRNAs in nicotine-related cancer pathogenesis are also highlighted.