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Current experimental stroke research has evolved to focus on detailed understanding of the brain's self-protective and restorative mechanisms, and harness this knowledge for development of new therapies. In this context, the role of peptidases and neuropeptides is of growing interest. In this focused review, peptidase neurolysin (Nln) and its extracellular peptide substrates are briefly discussed in relation to pathophysiology of ischemic stroke. Upregulation of Nln following stroke is viewed as a compensatory cerebroprotective mechanism in the acute phase of stroke, because the main neuropeptides inactivated by Nln are neuro/cerebrotoxic (bradykinin, substance P, neurotensin, angiotensin II, hemopressin), whereas the peptides generated by Nln are neuro/cerebroprotective (angiotensin-(1-7), Leu-/Met-enkephalins). This notion is confirmed by experimental studies documenting aggravation of stroke outcomes in mice after inhibition of Nln following stroke, and dramatic improvement of stroke outcomes in mice overexpressing Nln in the brain. The role of Nln in the (sub)chronic phase of stroke is less clear and it is likely, that this peptidase does not have a major role in neural repair mechanisms. This is because, the substrates of Nln are less uniform in modulating neurorestorative mechanisms in one direction, some appearing to have neural repair enhancing/stimulating potential, whereas others doing the opposite. Future studies focusing on the role of Nln in pathophysiology of stroke should determine its potential as a cerebroprotective target for stroke therapy, because its unique ability to modulate multiple neuropeptide systems critically involved in brain injury mechanisms is likely advantageous over modulation of one pathogenic pathway for stroke pharmacotherapy.