Genera belonging to the family Rickettsiaceae, Rickettsia and Orientia, include human pathogens. The diseases they cause are referred to as rickettsioses in this chapter. They share three critical factors with implications in pathogenesis and immunity: (i) they are transmitted by arthropod vectors; (ii) they are obligate intracellular bacteria that inhabit the cell cytoplasm; and (iii) the predominant target is the endothelium. The only exception is Rickettsia akari, the agent of rickettsial-pox, which predominantly infects monocytes and macrophages. The chapter emphasizes on some findings and suggests a framework for a modern conceptualization of the field of rickettsiology at the interface with immunology. The development of the adaptive immune response is conditioned by the innate immune mechanisms activated during early events of the infection. The study of the endothelium in the context of true endothelium-target infections offers new opportunities to explore the role of the endothelium in orchestrating or modifying immune responses. The study of the response to two of the most successful human vaccines in history, the yellow fever vaccine and the smallpox vaccine, is likely to yield relevant paradigms that we could use as guideposts in rickettsiology. Development of a modern vaccine against Rickettsiaor Orientia should aim at mimicking a physiological immune response in the sense that all branches of adaptive immunity should be stimulated. This implies the identification of a combination of antigens that together can stimulate protective responses mediated by CD8+ T cells, CD4+ T cells, and B cells (antibodies).