Animal models in the PK/PD evaluation of antimicrobial therapy have proven to be a critical element in drug development and dosing refinement for numerous infectious diseases. There are several variables that are taken into consideration when animal models are utilized. These can include host-specific variables such as the animal species, route of infection, infection site, immune status, end organ/tissue sampling and optimal endpoint measure. Pathogen-specific variables include the genus/species, inoculum size, virulence, and drug susceptibility. Finally, therapeutic variables include route of drug administration, timing of therapy, dose level and frequency, metabolism and elimination, and duration of therapy. This list of variables may seem challenging; however, carefully controlled animal model studies are the cornerstone of PK/PD therapeutic evaluations that lead to dosing regimen optimization, limiting drug-related toxicity, guiding therapeutic drug monitoring, and setting of drug susceptibility breakpoints.