The aim of the work was to substantiate the forecast of the epidemiological and epizootiological situation in natural foci of plague in the Russian Federation, countries of the near and far abroad for the year of 2021. Characteristics of the distribution of Yersinia pestis strains of the main subspecies (subspecies pestis) of medieval and antique biovars, Caucasian (ssp. caucasica) and central Asian (ssp. central asiatica) subspecies by 45 natural foci of the CIS countries are presented in the paper. The persistence of a multidirectional trend in the dynamics of epizootic activity of natural foci of the CIS countries with the circulation of Y. pestis pestis strains of the medieval biovar of the 2.MED1 phylogenetic branch and the antique biovar of the 0.ANT5, 4.ANT phylogenetic branches in the current decade has been outlined. For the Russian Federation, the development of epizootics is predicted in the Gorno-Altai highland and Tuva mountain natural foci caused by the circulation of Y. pestis pestis strains of the antique biovar 4.ANT and Y. pestis of the Altai biovar of the Central Asian subspecies 0.PE4a in 2021. For the Republic of Kazakhstan, there is a high probability of preserving epizootic activity in the North Aral, Aral-Karakum, Balkhash, Mojynkum, Taukum desert and Ili intermountain natural foci with the circulation of Y. pestis pestis strains of the medieval biovar of the phylogenetic branch 2.MED1. For the Kyrgyz Republic, the forecast for the development of plague epizootics caused by Y. pestis pestis strains of the antique biovar 0.ANT5 phylogenetic branch in the Sarydzhaz and Upper Naryn high-mountain natural foci has been substantiated. A high epidemic risk of epizootic manifestations caused by highly virulent strains of Y. pestis pestis of antique biovars 0.ANT5, 4.ANT and medieval biovar 2.MED1 for the entire territory of the CIS countries is noted. The relevance of implementing forecasts of the epidemiological situation into practice, taking into account the molecular-genetic and epidemiological characteristics of Y. pestis strains circulating in areas of expected epizootic manifestations of plague, is highlighted.