Cryptosporidium parvum, the protozoan responsible for cryptosporidiosis, continues to defy eradication with existing therapies. A review of the anticryptosporidial activity of several drugs in the dexamethasone-immunosuppressed rat model illustrates the multitude of factors that may contribute to the difficulty of assessing a drug’s therapeutic efficacy against the protozoan and provides possible explanation for drug failure at the level of host-parasite interaction.