Brucellosis is a global disease of domestic and wild mammals that is caused by intracellular bacteria of the genus Brucella. Although humans are not a natural reservoir for Brucella, infection in the human population is common in many countries, and brucellosis is one of the most common zoonotic infections. Brucella species have evolved to avoid the host's immune system and infection is usually characterized by long-term persistence of the bacteria. One important Brucella virulence factor for intracellular survival and persistence in the host is the type IV secretion system. This review will discuss the Brucella type IV secretion system in detail, including current knowledge of architecture and regulation, as well as the newly identified effector substrates that this system transports into host cells.