Background and Aim:Brucella species., as animal pathogens, are small, gram-negative, non-motile, non-spore-forming, facultative intracellular coccobacilli, and cause human brucellosis those results in worldwide economic losses and human morbidity. Out of 10 classified Brucella species, B. melitensis, B. abortus, B. suis, and B. canis are pathogenic for humans and B. melitensis remains the principal cause of human brucellosis. There are no safe and licensed vaccines for prevention of human brucellosis and the bacteria do not display obvious classic virulence factors such as exotoxins, capsule, and LPS. So the present study provides a comprehensive review of Brucella pathogenesis, with the goal to cover clinical aspects of the disease in humans. Methods:After investigating the pathogenic potential of Brucella spp. in humans, this study focused on the major mechanisms of Brucella pathogenesis, and divided them into two main categories and four steps. Results:Invasion to host cell and intracellular survival or replication are two major virulence mechanisms of Brucella pathogenesis and their steps included: adherence, invasion, establishment, and dissemination within the host. Then, the bacteria begin to infect the phagocytic and non-phagocytic cells of the reticuloendothelial system and finally can establish a chronic infection in humans. Conclusion:The mechanisms of Brucella pathogenesis are extremely related to its ability to enter and survive within host cells. Understanding these mechanisms can be useful not only for the development of new and improved vaccines or therapeutic methods, but also as tools for the study of components and regulation of the host immune system

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