Purpose 13C magnetic resonance spectroscopy (MRS) in combination with infusion of 13C‐labeled substrates has led to unique insights into human brain metabolism and neurotransmitter cycling. However, the low sensitivity of direct 13C MRS and high radiofrequency power requirements has limited 13C MRS studies to predominantly data acquisition in large volumes of the occipital cortex. The purpose of this study is to develop an MRS technique for localized detection of 13C‐labeling of glutamate and glutamine in the human frontal lobe. Methods We used an indirect (1H‐13C), proton‐observed, carbon‐edited MRS sequence (selPOCE) for detection of 13C‐labeled metabolites in relatively small volumes located in the frontal lobe at 4 T. The SelPOCE method allows for selective and separate detection of glutamate and glutamine resonances, which significantly overlap at magnetic field strengths used for clinical MRI. Results Phantom data illustrate how selPOCE can be tuned to selectively detect 13C labeling in different metabolites. Three‐dimensional specific absorption rate simulations of radiofrequency power deposition show that the selPOCE method operates comfortably within the global and local Food and Drug Administration specific absorption rate guidelines. In vivo selPOCE data are presented, which were acquired from a 45‐mL volume in the frontal lobe of healthy subjects. The in vivo data show the time‐dependent 13C‐labeling of glutamate and glutamine during intravenous infusion of 1‐13C‐glucose. Metrics describing spectral fitting quality of the glutamate and glutamine resonances are reported. Conclusions The SelPOCE sequence allows the detection of 13C‐labeling in glutamate and glutamine from a relatively small volume in the human frontal lobe at low radiofrequency power requirements. Magn Reson Med 80:11–20, 2018. © 2017 International Society for Magnetic Resonance in Medicine.