Yersinia pestis (Y. Pestis) is an infamous pathogen causing plague pandemics throughout history and is a selected agent of bioterrorism threatening public health. Y. pestis was first isolated by Alexandre Yersin in 1894 in Hong Kong and in the following years from all continents. Plague is enzootic in different rodents and their fleas in Africa, North and South America, and Asia, including the Middle/Far East and ex-USSR countries. Comprehending the multifaceted interaction between Y. pestis and the host immune system will enable us to design more effective vaccines. Innate immune response and both components (humoral and cellular) of adaptive immune response contribute to host defense against Y. pestis infection, but the bacterium possesses different mechanisms to counteract the immune response. The review aims to analyze the role of immune response versus Yersinia pestis infection and to highlight the various stratagems adopted by Y. pestis to escape the immunological defenses.