This study investigates the reprogramming of neural stem (NS) cells to a ground state of pluripotency using signal inhibition. NS cells were efficiently converted to a pluripotent state after a single round of transduction with reprogramming factors, but critical pluripotency markers were not fully achieved. By applying molecularly defined conditions, including dual inhibition of mitogen-activated protein kinase (Mek) and glycogen synthase kinase-3 (Gsk3) pathways, along with the self-renewal cytokine leukemia inhibitory factor (LIF), NS cells were able to achieve stable expression of pluripotency genes, reactivation of the X chromosome, and competence for somatic and germline chimaerism. The study shows that NS cells require fewer transgene integrations and can be efficiently reprogrammed without the need for Sox2 or c-Myc. The findings demonstrate that the somatic cell state influences reprogramming requirements and reveal two phases in the process. The ability to capture pre-pluripotent cells that can advance to ground state pluripotency simply and efficiently opens the door to molecular dissection of this phenomenon. The study also highlights that the use of 2i/LIF conditions allows for the efficient generation of authentic induced pluripotent stem (iPS) cells from NS cells, overcoming previous limitations in reprogramming efficiency and completeness. The results suggest that the reprogramming process can be significantly enhanced by blocking specific signaling pathways, leading to the generation of iPS cells with properties similar to embryonic stem cells. The study provides insights into the molecular mechanisms underlying reprogramming and the factors that influence the efficiency and completeness of the process.This study investigates the reprogramming of neural stem (NS) cells to a ground state of pluripotency using signal inhibition. NS cells were efficiently converted to a pluripotent state after a single round of transduction with reprogramming factors, but critical pluripotency markers were not fully achieved. By applying molecularly defined conditions, including dual inhibition of mitogen-activated protein kinase (Mek) and glycogen synthase kinase-3 (Gsk3) pathways, along with the self-renewal cytokine leukemia inhibitory factor (LIF), NS cells were able to achieve stable expression of pluripotency genes, reactivation of the X chromosome, and competence for somatic and germline chimaerism. The study shows that NS cells require fewer transgene integrations and can be efficiently reprogrammed without the need for Sox2 or c-Myc. The findings demonstrate that the somatic cell state influences reprogramming requirements and reveal two phases in the process. The ability to capture pre-pluripotent cells that can advance to ground state pluripotency simply and efficiently opens the door to molecular dissection of this phenomenon. The study also highlights that the use of 2i/LIF conditions allows for the efficient generation of authentic induced pluripotent stem (iPS) cells from NS cells, overcoming previous limitations in reprogramming efficiency and completeness. The results suggest that the reprogramming process can be significantly enhanced by blocking specific signaling pathways, leading to the generation of iPS cells with properties similar to embryonic stem cells. The study provides insights into the molecular mechanisms underlying reprogramming and the factors that influence the efficiency and completeness of the process.