For decades, numerous pharmacological and non-pharmacological strategies have been evaluated without success to limit the consequences of the ischemic cascade, but more rarely the therapies were explored as add on remedies on individuals also receiving reperfusion therapies. It is plausible that these putative neuroprotectants never reached the ischemic brain in adequate concentrations. Currently, the concept of neuroprotection incorporates cerebral perfusion as an obligatory substrate upon which ischemic brain survival depends, and it is plausible that some of the compounds tested in previous neuroprotection trials might have resulted in more favorable results if reperfusion therapies had been co-administered. Nonetheless, pharmacological or mechanical thrombectomy are frequently powerless to fully reperfuse the ischemic brain despite achieving a high rate of recanalization. This review covers in some detail the importance of the microcirculation, and the barriers that may hamper flow reperfusion at the microcirculatory level. It describes the main mechanisms leading to microcirculatory thrombosis including oxidative/nitrosative stress and refers to recent efforts to ameliorate brain perfusion in combination with the co-administration of neuroprotectants mainly aimed at harnessing oxidative/nitrosative brain damage.