The protective resolution of liver fluke (Fasciola hepatica and Fasciola gigantica) infection is a dynamic interplay between the host's effector responses and the parasite's defence and immunomodulatory systems. The evidence suggests that the juvenile or immature parasite is the target of protective host immune responses but the effector mechanisms employed vary between hosts. Moreover, F. hepatica and F. gigantica differ in their susceptibility to these killing mechanisms. In the rat, in vitro killing of juvenile F. hepatica involves an antibody-dependent cell cytotoxicity mediated by nitric oxide produced by activated monocytes and (or) macrophages. However, monocytes and (or) macrophages from Indonesian sheep do not produce nitric oxide yet can effectively kill juvenile F. gigantica in vitro and in vivo by a mechanism that is ineffective against F. hepatica. These data show that disease progression or resolution in fasciolosis is determined both by biochemical differences between Fasciola species and by host-dependent factors. Understanding the genetic basis for these differences is a key question for the future. Fasciola hepatica and F. gigantica actively modulate the host immune response, downregulating type 1 responses during infection. It is important to determine whether such modulation of the immune response by Fasciola spp. directly leads to enhanced parasite survival in the various hosts.