Plague has been a scourge of mankind for centuries, and outbreaks continue to the present day. The virulence mechanisms employed by the etiological agent Yersinia pestis are reviewed in the context of the available prophylactic and therapeutic strategies for plague. Although antibiotics are available, resistance is emerging in this dangerous pathogen. Therapeutics used in the clinic are discussed and innovative approaches to the design and development of new therapeutic compounds are reviewed. Currently there is no licensed vaccine available for prevention of plague in the USA or western Europe, although both live attenuated strains and killed whole-cell extracts have been used historically. Live strains are still approved for human use in some parts of the world, such as the former Soviet Union, but poor safety profiles render them unacceptable to many countries. The development of safe, effective next-generation vaccines, including the recombinant subunit vaccine currently used in clinical trials is discussed.