Chemical biosensors that can target analytes in a variety of biological fluids have been widely studied in recent decades. Extensive efforts have been made to design and build user-friendly, in situ tissue-interfaced biosensors with multiple integrated functions, miniaturized footprint and improved selectivity, sensitivity and stability. This review article presents the recent advances of these tissue-interfaced chemical biosensors. We start with a short introduction to the detection mechanism and design principles of soft chemical biosensors and then focus on the architectures, properties and applications of different types of such biosensors. The remaining challenges and future directions are finally highlighted for future research.