Ferrets are now being widely used to supplement or validate studies in mice, especially for H5N1 virus studies in order to comply with new FDA “two animal rule”. A tremendous advantage of ferrets is that these animals display many clinical symptoms of human influenza. The model also has a similar complexity to that of humans. However, as with the mouse model, many host factors found associated with humans are missing or have not yet been discovered in the ferret. The costs of ferrets, space needed for housing, temperament of the animal once handled experimentally, and the availability of animals without prior exposure to influenza remain of concern.