The revised Cryptosporidium life cycle offers opportunities for fundamental and translational advances.

Cryptosporidium is a leading cause of severe diarrheal disease, for which effective treatments and vaccines are lacking. The past decade has seen breakthrough advances in how the parasite and disease can be studied in the field and the laboratory. This has led to an increasingly molecular understanding of how parasite protein secretion orchestrates invasion and host-parasite interactions and to a revision of the Cryptosporidium life cycle. Parasite sex emerges as an engine of genomic innovation, allowing the parasite to adaptively evolve host specificity, virulence, and drug resistance. The unique importance of sex for Cryptosporidium also offers opportunities for forward genetic discovery and could provide new targets for treatment and prevention. Here, we review key concepts and discuss the outstanding questions critical to fundamental understanding and translational advancement.