The past decade has seen growing acceptance that glaucoma should be viewed as a slowly progressive neurodegenerative disease. According to this view, in glaucoma (as in other such diseases), whatever the primary risk factors, at any given time some neurons are still healthy but are threatened with destruction owing to the toxicity emanating from the degenerating neurons. It follows that any intervention that protects surviving neurons and rescues the marginally damaged ones should slow down progression of the disease. This novel view of glaucoma prompted scientists to compare glaucoma with other neurodegenerative diseases with respect to mediators of disease progression and ways in which the spread of damage, or 'secondary degeneration', can be attenuated. Studies of partial crush injury of the rat optic nerve, a model of secondary degeneration established in our laboratory, led us to conceptualize the 'enemy within' as a flood of neurotoxic self-compounds issuing from the degenerating nerve. With this model, pharmacological and molecular approaches were employed to identify and test potentially therapeutic neuroprotective compounds and methodologies, leading us ultimately to the serendipitous discovery of protective autoimmunity as the body's defense against destructive self-compounds. Mediators of self-perpetuating acute and chronic degeneration identified in the injured optic nerve were also detected in other sites of central nervous system (CNS) damage. This finding led scientists to screen drugs that had proven to be beneficial in other disease models for their use in glaucoma therapy. It also opened the way to studies of the direct effects of these toxic mediators on retinal ganglion cell survival and ways to prevent the degenerative outcome. Although no single model can fully simulate human glaucoma or any other neurodegenerative disease, the availability of different models of optic nerve damage and the similarity of findings in the optic nerve and in other parts of the CNS have led to significant progress toward development of a cure for glaucoma.