The main characteristics of a good pH detecting system are higher sensitivity, ease of manufacturing process, and a micro-system. Ion sensitive field effect transistors (ISFETs), which are frequently employed as biosensors, offer significant advantages, and have gained prominence in various sectors. This review has highlighted the factors influencing sensitivity in pH sensing and explored various methods to enhance the sensor’s sensitivity and overall performance. Miniature sensors play a crucial role, especially in industries, biomedical and environmental applications. For accurate pH measurements in both in-vivo and in-vitro systems, as well as for the device’s miniaturization, the reference electrode (RE) must be positioned precisely in an ISFET device, considering both the device’s physical dimensions and the distance between the sensing surface and the RE. Hence, this review provides valuable insights into the importance of sensitivity, miniaturization, and the role of the RE in ISFET devices, contributing to the advancement and application of pH sensing technology in
diverse fields.