Acanthamoeba keratitis is a sight-threatening infection of the ocular surface that is produced by several free-living amebae of the genus Acanthamoeba. Infection is usually initiated by Acanthamoeba-contaminated contact lenses and produces exquisite pain and ulceration of the ocular surface. The pathophysiology of this infection involves an intricate series of sequential events that includes the production of several pathogenic proteases that degrade basement membranes and induce cytolysis and apoptosis of the cellular elements of the cornea, culminating in dissolution of the collagenous corneal stroma. Targeting such proteases could lead to the development of vaccines that target the disease process rather than the pathogen itself.