Purpose Extracellular pH (pHe) is an important biomarker for cancer cell metabolism. Acido‐chemical exchange saturation transfer (CEST) MRI uses the contrast agent iopamidol to create spatial maps of pHe. Measurements of amide proton transfer exchange rates (kex) from endogenous CEST MRI were compared to pHe measurements by exogenous acido‐CEST MRI to determine whether endogenous kex could be used as a proxy for pHe measurements. Methods Spatial maps of pHe and kex were obtained using exogenous acidoCEST MRI and an endogenous CEST MRI analyzed with the omega plot method, respectively, to evaluate mouse kidney, a flank tumor model, and a spontaneous lung tumor model. The pHe and kex results were evaluated using pixelwise comparisons. Results The kex values obtained from endogenous CEST measurements did not correlate with the pHe results from exogenous CEST measurements. The kex measurements were limited to fewer pixels and had a limited dynamic range relative to pHe measurements. Conclusion Measurements of kex with endogenous CEST MRI cannot substitute for pHe measurements with acidoCEST MRI. Whereas endogenous CEST MRI may still have good utility for evaluating some specific pathologies, exogenous acido‐CEST MRI is more appropriate when evaluating pathologies based on pHe values. Magn Reson Med 79:2766–2772, 2018. © 2017 International Society for Magnetic Resonance in Medicine.