The field of infectious diseases is in urgent need of new approaches to antimicrobial therapy. Radio-immunotherapy (RIT) has evolved into successful therapy for certain malignancies. Published preclinical and clinical investigations have demonstrated that radiolabeled microorganism-specific antibodies localize to tissue sites of bacterial and fungal infection. The potential of RIT as an antimicrobial treatment strategy has not been developed clinically, which could reflect lack of awareness of the difficult problems in clinical infectious diseases by the nuclear medicine community and of RIT by the infectious diseases physicians. We have recently demonstrated the feasibility of using RIT for treating murine cryptococcosis using a monoclonal antibody to Crypto-coccus neoformans capsular glucuronoxylomannan labeled with Bismuth-213 or Rhenium-188. Subsequently, we showed the applicability of RIT to bacterial (Streptococcus pneumonia) and viral (HIV-1) infections. Treatment did not cause acute hematologic toxicity in treated animals. The mechanisms of RIT of infection include killing of microbial cells by ''direct hit'' and ''cross-fire'' effects, promotion of apoptosis-like death, cooperation with macrophages and modulation of the inflammatory response. RIT for infection is theoretically useful for any microbe susceptible to radiation, including bacteria, fungi, viruses and parasites. The promise of this technique is based on the fact that the technology is largely in place and that the only requirements are availability of microbe-specific monoclonal antibodies and suitable radionuclides. In fact, one could anticipate that targeting microbes will be easier than targeting neoplastic cells when the enormous antigenic differences between host and microbes are taken into consideration. However, considerable basic work remains to be done to ascertain the optimal conditions for the efficacy of RIT for infection.