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Oral and topical pre-exposure prophylaxis (PrEP) with antiretroviral drugs are novel biomedical interventions recently found to prevent HIV transmission among high-risk populations. In this review, we outline lessons learned from animal studies and discuss next steps in preclinical PrEP research including the study of new PrEP modalities, pharmacologic correlates of protection, and biological factors that may modulate PrEP efficacy.Studies using macaque or humanized mice models of mucosal simian immunodeficiency virus (SIV), HIV, or simian/human immunodeficiency virus (SHIV) transmission have provided efficacy data against rectal and vaginal infection. A multitude of oral and topical PrEP regimens including drugs such as tenofovir (TFV), tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) were tested against either wild-type or drug-resistant viruses. These models have also helped define prophylactic windows of protection of nondaily dosing and are being used increasingly to study pharmacokinetic and pharmacodynamic relationships.As human data from PrEP trials validate animal models or help fine tune them, it is expected that these models will play increasingly important roles in PrEP development as the field extends into new drug classes and combinations, episodic dosing, and novel long-acting drug formulations. By providing both efficacy and pharmacologic information these models can define correlates and mechanisms of protection, inform dose selection, and advance the most promising PrEP candidates and dosing modalities.