Parasitic diseases are a serious global health concern. Many of the most common and most severe parasitic diseases, including Chagas' disease, leishmaniasis, and schistosomiasis, are also classified as neglected tropical diseases and are comparatively less studied than infectious diseases prevalent in high income nations. The NLRs (nucleotide-binding domain leucine-rich-repeat-containing proteins) are cytosolic proteins known to be involved in pathogen detection and host response. The role of NLRs in the host response to parasitic infection is just beginning to be understood. The NLR proteins NOD1 and NOD2 have been shown to contribute to immune responses during Trypanosoma cruzi infection, Toxoplasma gondii infection, and murine cerebral malaria. The NLRP3 inflammasome is activated by T. cruzi and Leishmania amazonensis but also induces pathology during infection with schistosomes or malaria. Both the NLRP1 and NLRP3 inflammasomes respond to T. gondii infection. The NLRs may play crucial roles in human immune responses during parasitic infection, usually acting as innate immune sensors and driving the inflammatory response against invading parasites. However, this inflammatory response can either kill the invading parasite or be responsible for destructive pathology. Therefore, understanding the role of the NLR proteins will be critical to understanding the host defense against parasites as well as the fine balance between homeostasis and parasitic disease.