For nearly 50 years, nuclear medicine has played an important role in the diagnosis of infection. Gallium citrate Ga 67 was one of the first, if not the first, radionuclide used for this purpose. Unfavorable imaging characteristics, a lack of specificity, and the long interval (2-3 days) between administration and imaging spurred the search for alternatives. At the present time, gallium 67 citrate is used primarily for differentiating acute tubular necrosis from interstitial nephritis and as an alternative for indications including sarcoid, spondylodiscitis, and fever of unknown origin, when 18F-fluorodeoxyglucose (18F-FDG) is not available. The approval, in the mid-1980s, of techniques for in vitro labeling of leukocytes with indium-111 and technetium-99m that subsequently migrate to foci of infection was a significant advance in nuclear medicine imaging of infection and labeled leukocyte imaging still plays an important role in imaging of infection. There are significant disadvantages to in vitro labeled leukocyte imaging. Unfortunately, efforts devoted to developing in vivo leukocyte labeling methods have met with only limited success. Over the past 20 years 18F-FDG has established itself as a valuable imaging agent for musculoskeletal and cardiovascular infections, as well as sarcoidosis and fever of unknown origin. As useful as these agents are, their uptake is based on the host response to infection, not infection itself. Previous attempts at developing infection-specific agents, including radiolabeled antibiotics and vitamins, were limited by poor results and/or lack of availability, so investigators continue to focus on developing infection-specific nuclear medicine imaging agents.