Endogenous neuroprotection was mostly investigated in stroke, trauma and neurodegenerative diseases. However, several endogenous neuroprotective mechanisms have been identified recently in multiple sclerosis: protective autoimmunity, direct low molecular weight antioxidants, indirect antioxidants inducing cytoprotective proteins, kynurenine pathways, ischemic preconditioning, integrated cell response, cannabinoids and complement system. Numerous endogenous neuroprotective strategies are investigated in animal models but the translation into the clinic of positive results obtained in the laboratory has been disappointing so far Endogenous neuroprotection is the net result of complex and interconnected mechanisms and modulating an individual neuroprotective pathway will likely yield a partial benefit, if any. Another concern, consistently observed in multiple sclerosis and its animal models, is that the same cells and the same chemical mediators can initiate degenerative cascades and/or neuroprotective pathways. The final outcome depends on the local microenvironment but most of the regulatory mechanisms that control the balancing of protective versus detrimental responses are unknown at present. Before experimental strategies are to become approved treatments further studies are necessary to understand the precise molecular mechanisms underlying neuroprotective pathways and their complex interconnections.