Cryptosporidium, a genus of protozoan parasites distributed worldwide, causes severe diarrhoea disproportionately affecting those with poor nutrition and/or immunodeficiency. The global enterics multi-center study (GEMS) found Cryptosporidium to be the second leading cause of moderate-to-severe diarrheal disease and the leading pathogen associated with mortality in 6-18 month-old children at sites in both Africa and Asia. The only drug for cryptosporidiosis, nitazoxanide, has only a 30% response rate in malnourished children and no efficacy in HIV infected individuals. Improved therapeutics are the greatest hope in the near term for addressing death and disability from Cryptosporidium, and one of the unique challenges in drug development for cryptosporidiosis is that Cryptosporidium is largely localized to the gastrointestinal tract. The localization of the parasite adds complexity to prioritization of preclinical drug candidates, as not only are we unsure which PK/PD index should be used for predicting in vivo efficacy, it is also unclear which tissue drug concentration will provide the information required for predicting the desired in vivo response. Therefore, we investigated how differences in compound pharmacokinetics are associated with in vivo efficacy in a neonatal and adult mouse model of C. parvum infection. Based on this work, we have generated models that have allowed us to select efficacious dosing regimens prior to in vivo studies. In conclusion, the information on the importance of gastrointestinal drug exposure provided here will be valuable for the entire research community currently engaged in the development of therapeutics for cryptosporidiosis and other enteric diseases.