Ischemic stroke represents the 2nd leading cause of death worldwide and the leading cause for long-term disabilities, for which no cure exists. After stroke, neurons are frequently lost in the infarct core. On the other hand, other cells such as astrocytes become reactive and proliferative, disrupting the neurovascular unit in the lesioned area, especially in the aged brain. Therefore, restoring the balance between neurons and nonneuronal cells within the perilesional area is crucial for post stroke recovery. In addition, the aged post stroke brain mounts a fulminant proliferative astroglial response leading to the buildup of gliotic scars that prevent neural regeneration. Therefore, “melting” glial scars has been attempted for decades, albeit with little success. Alternative strategies include transforming inhibitory gliotic tissue into an environment conducive to neuronal regeneration and axonal growth by genetic conversion of astrocytes into neurons. The latter idea has gained momentum following the discovery that in vivo direct lineage reprogramming in the adult mammalian brain is a feasible strategy for reprogramming nonneuronal cells into neurons. This exciting new technology emerged as a new approach to circumvent cell transplantation for stroke therapy. However, the potential of this new methodology has not been yet tested to improve restoration of structure and function in the hostile environment caused by the fulminant inflammatory reaction in the brains of aged animals.