Various strains of Atlantic salmon exhibit different levels of susceptibility to infections with the ectoparasitic monogenean Gyrodactylus salaris. The basic mechanisms involved in this differential ability to respond to this monogenean were elucidated using controlled and duplicated challenge experiments. Highly susceptible East Atlantic salmon allowed parasite populations to reach up to 3000 parasites per host within 6 weeks, whereas less susceptible Baltic salmon never reached larger parasite burdens than 122 parasites per host during the same period. The present study, comprising immunohistochemistry and gene expression analyses, showed that highly susceptible salmon erected a response mainly associated with an increased expression of interleukin-1beta (IL-1beta), interferon-gamma (IFN-gamma), IL-10 and infiltration of CD3-positive cells in the epidermis of infected fins. Less susceptible salmon showed no initial response in fins but 3-6 weeks post-infection a number of other genes (encoding the immune-regulating cytokine IL-10, cell marker MHC II and the pathogen-binding protein serum amyloid A) were found to be up-regulated. No proliferation of epithelial cells was seen in the skin of less susceptible salmon, and IL-10 may play a role in this regard. It can be hypothesized that resistant salmon regulate the parasite population by restricting nutrients (sloughed epithelial cells and associated material) and thereby starve the parasites. In association with this 'scorched-earth strategy', the production of pathogen-binding effector molecules such as serum amyloid A (SAA) (or others still not detected) may contribute to the resistance status of the fish during the later infection phases.