<p>Nowadays, potentiometric ion sensors have been widely used in disease diagnostics. However, up to now, the clinical applications of these sensors have been mainly limited to detection of electrolytes. Hence, it is highly desired to address the sensor fabrication challenges, and further extend application scenarios of potentiometric sensors in clinical disease diagnosis. This review summarizes the fabrication procedures and the applications of various polymeric membrane-based potentiometric sensors in diagnosis of multi-diseases such as metabolism, respiratory system, circulation system, digestive system, urinary system, reproductive system and nervous system diseases in body fluids including peripheral blood, saliva, tear, sweat, semen, vaginal fluid, urine and interstitial fluid. Furthermore, the existing challenges and future prospects are provided. It can be expected that this review will shed new lights on the understanding of polymeric membrane potentiometric sensors and pave the way for the widespread applications of these chemical sensors in medical diagnostics and therapeutic monitoring.</p> Graphical Abstract <p></p>