Helminths are remarkably successful parasites that can invade various mammalian hosts and establish chronic infections that can go unnoticed for years despite causing severe tissue damage. To complete their life cycles, helminths migrate through multiple barrier sites that are densely populated by a complex array of hematopoietic and non-hematopoietic cells. While it is clear that type 2 cytokine responses elicited by immune cells promote worm clearance and tissue healing, the actions of non-hematopoietic cells are increasingly recognized as initiators, effectors and regulators of anti-helminth immunity. This review will highlight the collective actions of specialized epithelial cells, stromal niches, stem, muscle and neuroendocrine cells as well as peripheral neurons in the detection and elimination of helminths at mucosal sites. Studies dissecting the interactions between immune and non-hematopoietic cells will truly provide a better understanding of the mechanisms that ensure homeostasis in the context of helminth infections.