Plant pathogenic oomycetes, including biotrophic downy mildews and hemibiotrophs/ necrotrophs such as Phytophthora and Pythium, cause enormous economic losses on cultivated crops. Lettuce breeders and growers face the threat of Bremia lactucae, the causal agent of lettuce downy mildew. This pathogen damages leaf tissues and lettuce heads and is also frequent on wild Asteraceae plants. The interactions of Lactuca spp. with B. lactucae (abbr. lettuce-Bremia) display extreme variability, due to a long co-evolutionary history. For this reason, during the last 30 years, the lettuceBremia pathosystem has been used as a model for many studies at the population, individual, organ, tissue, cellular, physiological and molecular levels, as well as on genetic variability and the genetics of hostparasite interactions. The first part of this review summarizes recent data on host-parasite specificity, host variability, resistance mechanisms and genetics of lettuce-Bremia interactions. The second part focuses on the development infection structures. Phenotypic expression of infection, behaviour of B. lactucae on leaf surfaces, the process of penetration, development of primary infection structures, hyphae and haustoria are discussed in relation to different resistance mechanisms. In the third part, the components of host resistance and the variability of defence responses are analysed. The role of reactive oxygen species (ROS), antioxidant enzymes, nitric oxide (NO), phenolic compounds, reorganization of cytoskeleton, electrolyte leakage, membrane damage, cell wall disruption, hypersensitive reaction and plant energetics are discussed in relation to defence responses. In general, the extreme variability of interactions between lettuce and Bremia, and their phenotypic expression, results from diversity of the genetic background. Different mechanisms of resistance are conditioned by an orchestra of defence responses at the tissue, cell, and molecular levels. The various events responsible for defence involve a complex interaction of the processes and reactions mentioned above. This review also provides an overview on the timing of pathogen development, host pathological anatomy, cytology and physiology Eur J Plant Pathol (2008) 122:71-89 of lettuce-Bremia associations. The significance of these factors on the expression of different resistance mechanisms (non-host and host resistance, race-specific and race non-specific resistance, field resistance) is discussed.