Extracellular signal-regulated kinase (ERK) is a versatile protein kinase, which has been implicated in signaling numerous biological functions ranging from embryonic development to memory formation. Recent reports, including ours, indicate that ERK plays a central role in promoting neuronal degeneration in various neuronal systems including neurodegenerative diseases. Mechanisms involved in ERK-induced neuronal degeneration are beginning to emerge. In this review, we summarize evidence suggesting ERK to be a predominant inducer of a non-apoptotic mode of neuronal death. Further, we discuss the mechanisms and the putative molecular inter-players associated with ERK-mediated neuronal death.