The potential for carotenoids to modulate chronic diseases related to smoke is currently under investigation and renewed interest has been placed on achieving a better understanding of the mechanism(s) of action of carotenoids in smoke-exposed biological systems. Available data currently show that, while carotenoids alone are not harmful, their interaction with smoke may shift from beneficial to detrimental depending on the dose, the type of carotenoid as well as the biological environment in which they act. Several mechanisms have been proposed to explain such a shift. They include: (i) changes in cell oxidative status, which tips the beta-carotene antioxidant- prooxidant balance toward a prooxidant status; (ii) modulation of the levels of key proteins involved in the regulation of cell proliferation and apoptosis; (iii) reduction of retinoic acid signal pathway which down-regulates the RARbeta expression and up-regulates AP-1; (iv) interference with absorption of other nutrients at better antioxidant profile; (v) formation of specific carotenoid oxidation products. This review summarizes the available evidences in cultured cells, animal models and humans for a modulatory action of carotenoids on the dangerous effects of smoke and focuses on the main molecular pathways involved in this process.