Coxiella burnetii is an obligate intracellular bacterium that causes a worldwide zoonotic disease, Q fever. Since C. burnetii infection could develop into severe chronic disease in humans, vaccination is the logical approach to prevent individuals at risk of natural and deliberate exposure. Although formalin-inactivated C. burnetii phase I vaccine (PIV) is effective in protecting vaccinated host against the infection in humans, widespread use of this vaccine is limited by its high incidence of adverse reactions, especially in individuals with prior immunity to the agent. Creation of a safe and effective vaccine to prevent Q fever remains an important goal for public health and international biosecurity. It is critical to clearly understand the mechanisms that involved in development of protective immunity against C. burnetii infection and to identify the key protective antigens for developing a safe and effective new generation vaccine against Q fever. This chapter describes new information related to the characterization of acquired immunity to C. burnetii vaccination and infection that will provide a fundamental understanding of the development of protective immunity against Q fever.