The protozoan parasite Cryptosporidium is a leading cause of severe diarrhea in young children and an important contributor to early childhood mortality. Fully effective drugs and vaccines to treat or prevent cryptosporidiosis are lacking. A main roadblock for their development has been the overall poor tractability of this parasite. We established molecular genetic as well as natural infection animal models to overcome this hurdle. Using these systems we can now engineer reporter parasites to derive robust measurements of infection in vitro and in vivo as well as parasite mutants to reveal the function of Cryptosporidium genes and proteins. We are using these tools to understand fundamental parasite biology. How does the parasite’s complex sexual lifecycle unfold, and how do parasite and host interact to shape susceptibility, disease and protection in the intestinal epithelium?