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Leptospirosis is a globally important zoonotic disease that affects humans on all continents, in both urban and rural contexts, and in temperate and tropical climes. Leptospirosis is a disease of the environment; transmission depends on interactions between humans and mammalian reservoir hosts. A variety of infectious diseases that present as undifferentiated febrile syndromes, such as malaria, dengue and influenza, as well as viral hemorrhagic fevers can mimic leptospirosis. The importance of pulmonary hemorrhage as a lethal complication of leptospirosis has become more widely recognized. In contrast to textbook dogma, population-based studies indicate that there is a poor correlation between infecting leptospiral strain and clinical expression of disease. Genetic transformation of a Leptospira sp. has now been reported, which should allow for detailed analysis of a variety of leptospiral genes. Publication of the whole Leptospira genome is eagerly awaited. Following recent reports of a new, highly effective conjugate typhoid vaccine, new efforts to find leptospirosis vaccines should include the manufacture and testing of conjugate leptospiral lipopolysaccharide vaccines. Recent advances, particularly in epidemiology, molecular genetics and pathogenesis, are placing leptospirosis at the cutting edge of biomedical science.