NADPH is a critical metabolite for biosynthesis and antioxidant defense that can be generated through multiple pathways. We discovered that, surprisingly, quiescent fibroblasts activate the NADPH-producing enzyme glucose-6-phosphate dehydrogenase (G6PD), despite their reduced need for nucleotides generated from the oxidative pentose phosphate pathway. The NADPH produced in the quiescent fibroblasts is associated with higher activity of glutathione reductase and higher ratios of reduced to oxidized glutathione. The NRF2 transcription factor transcriptionally regulates G6PD and isocitrate dehydrogenase (IDH). Inhibition of G6PD or NRF2 results in oxidative stress and apoptosis selectively in quiescent fibroblasts. Applying in situ metabolic activity assays, we found the nondividing, differentiated cells of the hair follicle have high potential for G6PD activity, while the quiescent hair follicle bulge cells have high IDH activity potential. Surprisingly, the proliferative cells within the hair follicle exhibited little potential for either G6PD or IDH. Induction of squamous cell carcinoma resulted in increased potential for both G6PD and IDH activity in the stem cells, their proliferating progeny and surrounding fibroblasts. Our findings demonstrate that different NADPH production pathways are activated in different cellular contexts and raise the possibility that inhibition of such pathways could prevent or reverse tumorigenesis.