Cryptosporidium spp. (C. hominis and C. parvum) are a major cause of diarrhea-associated morbidity and mortality in young children globally. While C. hominis only infects humans, C. parvum is a zoonotic parasite that can be transmitted from infected animals to humans. There are no treatment or control measures to fully treat cryptosporidiosis or prevent the infection in humans and animals. Our knowledge on the molecular mechanisms of Cryptosporidium-host interactions and the underlying factors that govern infectivity and disease pathogenesis is very limited.Recent development of genetics and new animal models of infection, along with progress in cell culture platforms to complete the parasite lifecycle in vitro, is greatly advancing the Cryptosporidium field.In this review, we will discuss our current knowledge of host-parasite interactions and how genetic manipulation of Cryptosporidium and promising infection models are opening the doors towards an improved understanding of parasite biology and disease pathogenesis.