With growing demand for environmental analysis as well as monitoring and process control systems, development of cost-effective sensors and sensor systems is becoming more and more important. Electrochemical sensors based on chalcogenide glasses (ChG) are becoming widely used for practical purposes, such as for waste, industrial and sea water analyses, in doping control of ultrapure metal production, and in multisensor “electronic tongue” systems. An ion-selective electrode (ISE) is a transducer (or sensor) that converts the activity of a specific ion dissolved in a solution into an electrical potential difference, which can be measured by a voltmeter or pH meter. The potential difference is theoretically dependent on the logarithm of the ionic activity, according to the Nernst equation. The sensing part of the electrode is usually made from an ion-specific membrane, along with a reference electrode. Chalcogenide glass materials represent one class of membranes with a high electrochemical performance, good chemical durability and excellent lifetime in comparison with their organic counterparts, such as polymeric membranes in combination with ionophores. This chapter discusses potentiometric sensor electrodes, many of which are commonly known as ion-selective electrodes (ISE), although a class of decidedly non-selective potentiometric sensor electrodes is also becoming quite important. The basic principles for operation of electrochemical sensors, with emphasis on chalcogen based membranes for various applications, are discussed.