Re-emergence of human cases of plague after decades of silence does not necessarily mean that plague foci are re-emerging. Most often, Yersinia pestis bacteria have been maintained and circulating at low levels in the rodent populations. It seems therefore more appropriate to speak in terms of expansion or regression phases for sylvatic rodent plague foci and to reserve the term re-emergence for human cases. From the analysis of well-documented human plague cases in Madagascar, we underline the causes of re-emergence that can be generalized to most world foci, and can help define environments at risk where the threat of new emergence lurks. In all recent plague outbreaks, usually more than one risk factor was at the origin of the re-emergence. The reduction or discontinuance of surveillance and control, as well as poverty and insalubrity are the main factors in the re-emergence of human cases, allowing increased contacts with infected rodents and fleas. Environment changes (i.e. climatic changes, deforestation, urbanization) induce changes in flea and rodent populations by (i) extension of rodent habitats (for example by replacing forests by steppes or farmlands); (ii) modifications in population dynamics (possible outbreaks due to an increase of available food resources); but also, (iii) emergence of new vectors, reservoirs and new Y. pestis genotypes. Numerous and spontaneous genomic rearrangements occur at high frequencies in Y. pestis, which may confer selective advantages, enhancing the ability of Y. pestis to survive, to be transmitted to new hosts, and to colonize new environments. Therefore, any environmental change should be taken as a warning signal and active surveillance programs should be initiated.