The invention of sensors that can identify and measure biomolecules is a key advancement for biology. Sensors have become widely used in several industries during the last few decades, most notably in the area of medical diagnosis. Biosensors constitute a bio detecting system by the integration of signal conversion and biological recognition components. They have been developed for a wide range of bio detecting applications. A class of biosensors, known as electrochemical biosensors, which use electroanalytical equipment and have the advantages of higher sensitivity, simplicity, speed as well as biomolecule recognition selectivity. One of the most popular electrochemical biosensors nowadays is ISFET sensor, which serves for both biochemical measuring and biomolecules recognition. ISFETs, which were first suggested a little over fifty years ago, now the most promising devices for care diagnostics and lab on a chip are made with ISFETs. In this review paper, history, working principles, fabrication processes, and modelling and simulation techniques of ISFET are presented. Additionally, some physical aspects and simulation methodologies are explained. Finally, we discuss their applications to analyse diverse biomolecules, including DNA, enzymes, and cells, in a sensitive and reliable manner.