The rise of multi-drug resistant pathogenic microorganisms has led to searches for alternative antimicrobial therapies to treat infections. Photodynamic therapy (PDT) is a rapidly expanding approach to the treatment of infections because it may be able to eliminate infectious microbial cells without causing undue damage to host tissue and is thought to be unlikely to induce PDT resistance. In order to develop PDT as a new therapy for infections, we need to demonstrate that PDT can indeed accomplish these aims in living hosts. Animal models of infection represent a powerful tool to dissect the natural history of infection, investigate the pathogenicity and virulence of the microbes, as well as measure the efficacy of PDT. This chapter will discuss the use of animal models for evaluating PDT of various types of localized infections.