Despite major advances in our understanding of the initiating factors that trigger many neurodegenerative disorders, to date, no novel disease-modifying therapies have been shown to provide significant benefit for patients who suffer from these devastating disorders. As most neurodegenerative disorders are late-onset, slowly progressive, and appear to have long relatively asymptomatic prodromal phases, it is possible that therapies optimally targeting the triggers of these disorders may have limited benefit when treatment is initiated in the symptomatic patient. Such therapies may work in the prodromal phase, or when given prophylactically, but in the symptomatic patient there simply may be too much damage to the neuronal networks to restore functionality by reducing or even eliminating the primary stressor. As functional neuronal demise and overt neuronal death are almost certainly the key factors that mediate the functional impairment, it is clear that preventing neuronal death and dysfunction will have a huge clinical benefit. Unfortunately, we lack a detailed understanding of neuronal death pathways in almost all neurodegenerative disorders. To rationally develop new disease modifying therapies that target steps in the degenerative cascade downstream of the disease trigger will require a number of factors. First, we need to refocus our basic research efforts on identifying the precise steps in the pathological cascade that lead to neuronal death in each neurodegenerative disease and, if possible, determine the relative placement of those events within a potentially very complex cascade. Second, we will need to determine which of these steps are potentially targetable. Finally, we will need to develop novel therapies that interfere with these steps and demonstrate that such therapies alone, or in combination with therapies that target the trigger of these devastating diseases, have clinical benefit.