Real-time analyses of routes of infection, tissue colonization, gene expression and response to antibiotic therapy would reveal much about mechanisms of pathogenesis, tempo of disease progression and therapeutic interventions. We have developed a method by which light from tagged biological processes, labeled by expressing bioluminescent proteins(luciferase), can be used to noninvasively monitor the distribution of pathogens and gene expression in living laboratory mammals. In a mouse model of human typhoid fever, abortive Salmonella infections in mice could be distinguished from those that were persistent or progressive. The effect of antibiotic therapy on infection was observed within minutes of treatment and the response could be noninvasively followed over several hours, permitting rapid evaluation of pharmacokinetics and efficacy. Modifications of the technique also permit noninvasive monitoring of mammalian gene expression such that developmental regulation, host response to pathogens and in vivo delivery of therapeutic genes can be studied. This approach will facilitate development of novel therapeutic compounds and accelerate drug evaluation in animal models. The increased understanding gained by viewing the spatio-temporal distribution of pathogens in living animal models for human disease will likely have a significant impact on how we hreat infections in humans.