This chapter reviews the changing epidemiology of plague over the past several decades and discusses factors of plague emergence or re-emergence. Three biotypes of Yersinia pestis, classified according to their ability to ferment glycerol and reduce nitrate, are correlated with the three major plague pandemics of history. Effective strategies to prevent and control the spread of plague were made possible by an understanding of its ecology and epidemiology. Epidemiologic investigations revealed that, with rare exception, human-to-human plague transmission occurs only as a result of close contact of persons with a case of pneumonic plague and that contagious spread could be interrupted by isolating plague patients. Many of the natural foci of plague are being increasingly invaded by humans and are undergoing dramatic man-made environmental changes. Under some circumstances, a changing rural environment such as suburbanization in the southwestern United States may increase human risk. An important factor today in the epidemiology of plague is its entrenchment in natural rural cycles. The ability to detect, monitor, and respond to plague is based on a solid public health infrastructure. In addition to routine laboratory studies, there is an important role for advanced genetic techniques to define the molecular epidemiology of plague and to detect and characterize newly evolving traits, such as virulence factors and factors associated with antimicrobial resistance.