This presentation will overview tumor extracellular pH mapping using electron paramagnetic resonance (EPR) and pH-sensitive imaging agents. Tumor acidification is a hallmark of solid malignant tumors and is related to hypoxia-induced metabolic shifts. Therefore, the measurement and visualization of extracellular pH (pHe) are essential for researchers to understand the tumor pathophysiology and microenvironment. While EPR has been used for pH measurements of mouse tumor models, that method is not sensitive enough to map tumor pHe with a moderate amount of imaging agents. Here, we show the modified EPR imaging system with a two-fold sensitivity enhancement using multiple harmonic detections. After demonstrating the solution pH mapping, we present tumor extracellular pH mapping for a mouse xenograft model of human-derived pancreatic ductal adenocarcinoma cell line MIA PaCa-2. Furthermore, we monitor the tumor pHe response in the MIA PaCa-2 mouse xenograft model to the treatment of carbonic anhydrase IX (CAIX) inhibitor U-104. Tumor growth delay and a concurrent tendency toward further extracellular acidification are shown with the U-104 treatment. We show that EPR-based tumor pHe mapping successfully monitored the tumor response to pharmacological intervention.