Nearly a billion-people suffer from allergies, resulting in considerable morbidity and poor quality of life. With the highest prevalence in the world, the cost of allergic diseases in Australia is over $9 billion per year. Specific bacterial species and low microbial diversity have been associated with allergy. Among the factors that influence microbial colonization, maternal diet, mode of delivery, absence of breastfeeding and antibiotics have been identified. Several clinical and experimental studies have shown that live helminth therapy, hookworms in particular, ameliorates chronic inflammatory diseases by promoting regulatory immune circuits, particularly the induction of regulatory T cells (Tregs) and the modification of the intestinal microbiome. Much of this immunomodulatory function can be attributed to the secretion of helminth proteins into host tissues. We have recently reported that the hookworm-derived anti-inflammatory proteins (AIP) induce the expansion of Tregs that promote long-term protection against allergic asthma and colitis in mice, both therapeutically and prophylactically. In addition, AIP induced similar immunomodulatory mechanisms in cells from allergic patients. Treatment with the hookworm proteins modulated the mucosal production of regulatory and inflammatory processes likely promoting rapid tissue healing. Hookworm recombinant proteins are a novel therapeutic modality with the potential to profoundly impact the management and progression of chronic inflammatory diseases.