The cerebrum, as the substrate for our consciousness, memories, personality, and self-identity, presents unique challenges for regenerative medicine. Regenerative approaches must not only maintain general cerebral function, but also preserve as much as possible the details of the wiring and firing parameters that define each individual. A combination of molecular repair and gradual cellular replacement appears most likely to succeed. Toward this end, we are establishing paradigms in mice for replacing glutamatergic projection neurons in the neocortex, seat of our highest cognitive functions. Any strategy for using transplanted cells for neocortical cell replacement is currently hampered by the inability to get cells to disperse into the existing neural tissue. To overcome this issue, we will transplant at the edge of the neocortex highly migratory embryonic GABAergic precursor cells that are engineered with lentiviruses to transdifferentiate to a glutamatergic fate once they have dispersed throughout the neocortex. In a second set of experiments, we have successfully used two independent transgenic approaches to induce apoptosis in small numbers of neurons in the absence of major inflammation (unlike for stroke or injury for example) to determine if under these conditions endogenous stem cells can be activated to replace dying neurons. These mice also provide a potentially ideal host environment for our transplanted migratory precursors. Preliminary results will be presented. Furthermore, even if our efforts are successful in generating new glutamatergic neurons, these replacement paradigms will unlikely in themselves provide the means for complete neocortical rejuvenation. Other aspects of cortical regeneration that will also need to be addressed will be discussed.