In summary, our findings show that a ubiquitous overexpression of ERK2wt is severely detrimental in ischemic stroke, whereas an overexpression of the endogenous ERK1/2 inhibitors RKIP and its phosphorylation-deficient mutant RKIPS153A improve stroke outcome for at least up to three days after I/R. Here, MAPK3 is linked to ischemic stroke.