Apoptosis research in the past two decades has provided an enormous insight into its role in regulating cell death. However, apoptosis is only part of the story, and inhibition of neuronal necrosis may have greater impact than apoptosis, on the treatment of stroke, traumatic brain injury, and neurodegenerative diseases. Since the "calpain-cathepsin hypothesis" was first formulated, the calpain- and cathepsin-mediated regulation of necrotic cascades observed in monkeys, has been demonstrated to be a common neuronal death mechanism occurring from simpler organisms to humans. However, the detailed mechanism inducing lysosomal destabilization still remains poorly understood. Heat-shock protein-70 (Hsp70) is known to stabilize lysosomal membrane and protect cells from oxidative stress and apoptotic stimuli in many cell death pathways. Recent proteomics approach comparing pre- and post-ischemic hippocampal CA1 neurons as well as normal and glaucoma-suffered retina of primates, suggested that the substrate protein upon which activated calpain acts at the lysosomal membrane of neurons might be Hsp70. Understanding the interaction between activated calpains and Hsp70 will help to unravel the mechanism that destabilizes the lysosomal membrane, and will provide new insights into clarifying the whole cascade of neuronal necrosis. Although available evidence is circumferential, it is hypothesized that activated calpain cleaves oxidative stress-induced carbonylated Hsp70.1 (a major human Hsp70) at the lysosomal membrane, which result in lysosomal rupture/permeabilization. This review aims at highlighting the possible mechanism of lysosomal rupture in neuronal death by a modified "calpain-cathepsin hypothesis". As the autophagy-lysosomal degradation pathway is a target of oxidative stress, the implication of autophagy is also discussed.