Chronic exposure to cigarette smoke (CS) generally confronts cellular defense systems with one of the strongest known environmental challenges. In particular, the continuous exposure of tissues of the respiratory tract to abundant concentrations of radicals; volatile compounds of the gas phase, mainly reactive oxygen and nitrogen species; and CS condensate deposits trigger a pleiotropic adaptive response, generally aimed at restoring tissue homeostasis. As documented by numerous studies published over the past decade, a hallmark of this defense system is the activation of the transcription factor NF-E2-related factor 2 (Nrf2), which, consequent to its established role as master regulator of the cellular antioxidant response, has been shown to orchestrate the first line of defense against cell- and tissue-damaging components present in CS. The key to CS-dependent Nrf2 activation is assumed to be based on the long-known phenomenon of a general strong sulfhydryl (-SH) reactivity inherent to CS. This chemical trait is virtually predestined to be sensitized by the major route leading to Nrf2 activation, characterized by its dependence on the interaction of electrophiles with specific cysteine residues inherited by Nrf2's negative cytosolic regulator Keap1 (Kelch-like ECH-associated protein 1). In addition, other pathways involving CS-activated protein kinases implicated in the upstream regulation of Nrf2, such as protein kinase C, represent an alternative/complementary mechanism of CS-induced Nrf2 activation. Because of the outstanding function of the Nrf2-Keap1 axis in defending cells and tissues against oxidant and chemical stress, either directly or indirectly via cross-talking with other defense pathways, changes in the Nrf2 or Keap1 genotype have long been associated with disease development. In terms of the two major smoking-related diseases of the lung, that is, emphysema and lung cancer, a fully functional Nrf2 genotype seems to be necessary, although not sufficient by itself, to protect the smoker from acquiring emphysema. Contrasting with this protective role, however, Nrf2 function may be potentially fatal in smoking-related lung tumorigenesis: as concluded from recent clinical investigations, lung tumor tissues harbor increased mutation or, alternatively, aberrant expression rates in either the KEAP1 or the NRF2 gene, generally resulting in constitutive Nrf2 activation, suggesting that "abuse" of Nrf2 function is an advantageous strategy of the (developing) tumor to protect itself against oxidative stress in general. On the basis of the fundamental significance of the Nrf2 pathway in smoking-dependent disease development, several attempts have been described for dietary and pharmacological intervention, the majority of which are intended to activate Nrf2 aiming at emphysema prevention. The intention of this review is to compile and discuss the various aspects of CS-Nrf2/Keap1 interaction in terms of mechanism, disease development, and chemoprevention.