The liver fluke, Fasciola hepatica, infects and completes its lifecycle in an extensive range of mammalian hosts, including humans, cattle, sheep, mice, alpaca and kangaroo. We believe that such remarkable success as a parasite demonstrates the evolution of effective mechanisms of evading or modulating host protective immune responses that permits long-term residency in varied mammalian hosts. This is illustrated by a potent suppression of host protective inflammatory responses within hours of infection with Fasciola parasites followed by the activation of Th2/regulatory immune responses. We have proposed that the modulation of host immune responses primarily resides with the molecules contained in the secretome of helminths as these interact with host immune cells and thus likely influence their function. Consequently, there exists a unique opportunity to exploit these molecules for the prophylactic and therapeutic treatment of human pro- and auto-inflammatory disorders (for example septic shock, transplant rejection and autoimmune disease). Advances in mass spectrometry- based proteomics have facilitated the detailed characterisation of helminth secretomes and have led to the characterisation of three immune-modulatory proteins secreted by F. hepatica; namely cathepsin L1, peroxiredoxin and helminth defence molecule. The potential of these proteins in the prevention of immune-mediated disease has been tested in a range of animal models. Our results suggest that a single helminth-secreted protein may be developed clinically to control human immune responses in a way that is conducive to the prevention of immune-mediated diseases.