Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are part of the Raf/MEK/ERK1/2 cascade and are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. Therefore, this study aimed to investigate the impact of ERK1/2 after cerebral ischemia using transgenic mice with ubiquitous overexpression of ERK2 or of the Raf kinase inhibitor protein (RKIP), an inhibitor of the ERK1/2 signaling cascade.