Significance Naïve embryonic stem cells are characterized by genome-wide low levels of cytosine methylation, a property that may be intrinsic to their function. We found that retinol/retinoic acid (vitamin A) and ascorbate (vitamin C) synergistically diminish DNA methylation levels and in doing so enhance the generation of naïve pluripotent stem cells. This is achieved by two complementary mechanisms. Retinol increases cellular levels of TET proteins (which oxidize DNA methylation), whereas ascorbate affords them greater activity by reducing cellular Fe ³⁺ to Fe ²⁺ . This mechanistic insight is relevant for the production of induced pluripotent stem cells used in regenerative medicine, and contributes to our understanding of how the genome is connected to extrinsic and intrinsic signals.