Cholera is one of the main causes of morbidity and mortality in some countries in Asia and Africa and represents a key indicator of social development. Recent evidence showing how the flexibility of the genome of Vibrio cholerae allows its survival in the aquatic environment and in the human host is reviewed. Available evidence is suggestive that human activity and its impact on global climate change may have some impact on cholera epidemiology. Consistent findings have been noted for an association between cholera transmission and El Niño Southern Oscillation, global changes in the nitrogen cycle and modifications of water temperature, water depth, rainfall, conductivity, and copepod counts. Presently, the complex interaction between the pathogen, the host, and the environment requires a multidisciplinary approach that takes advantage of scientific information and technological developments. Moreover, cholera is a good example of the need of a multisectorial approach, where political leaders, nongovernmental organizations, and society are involved, as lack of clean water and sanitation combined with poor environmental status determine transmission of the disease.