Leptospirosis is a zoonotic bacterial infection that is prevalent across all continents and is caused by pathogenic spirochaetes of the genus Leptospira. Although infection can be asymptomatic, symptomatic disease can vary in severity from mild to severe illness, the latter characterized by icterus and/or multi-organ dysfunction and potentially death. An estimated one million cases of leptospirosis occur globally each year, resulting in ~60,000 deaths. The pathogenesis of severe leptospirosis is poorly understood but is believed to involve an interplay between genetic predisposition, pathogen virulence and dysregulated immune responses that trigger a cytokine storm with associated immunoparesis. Leptospira are susceptible to several low-cost antibiotics, including benzyl penicillin, doxycycline, cephalosporins and macrolides, when used in the early phase of infection. Late disease with organ dysfunction is treated with supportive care, and the benefit of antibiotics during late disease is doubtful. Very few countries have licensed a vaccine for human leptospirosis, and available vaccines only protect against rodent-associated serogroups. Exposure control by behavioural modifications and personal protective measures are the major preventative measures in leptospirosis, and the efficacy of prophylactic antibiotics has not been confirmed in clinical trials. Future research is needed to accurately estimate leptospirosis disease burden across the globe, to understand the pathophysiology of severe leptospirosis to inform the design of targeted immunotherapies and vaccines, and to develop cost-effective and accurate point-of-care diagnostics.