Accumulating evidence suggests that axon and dendrite (or neurite) degeneration both in vivo and in vitro requires self-destructive programs independent of cell death programs to segregate neurite degeneration from cell soma demise. This review will deal with the mechanisms of neurite degeneration caused by several experimental paradigms including trophic factor deprivation and Wallerian degeneration as well as those under pathological conditions. The involvement of autophagy and mitochondrial dysfunction is emphasized in these mechanisms. The mechanisms through which protective agents including the Wld(s) protein rescue neurites from degeneration or fail to do so will be discussed.