Chemical gas sensors can have an enormous impact on optimizing complex processes as well as facilitate disease diagnosis. In this article, we demonstrate how sensing of gas molecules is influencing the next generation of engines for transportation applications, as well as in disease diagnosis. In such applications, the demands on sensors are quite extreme. Not only does the device have to detect the gas of interest with high sensitivity, it also has to discriminate against other species present in a complex environment, such as combustion exhaust and human breath. In addition, the sensors will need to have as small a footprint as possible in size and power requirements. With these varied requirements in mind, only electrochemical sensors have the potential to be practical. This article focuses on nitric oxide (NOx) and ammonia (NH3) sensor necessary for emission control of next generation, high efficiency, lean burn engines and nitric oxide (NO) sensor for breath analysis for diagnosis of respiratory diseases. In all of these applications, there has been significant recent commercial activity. We indicate the electrochemical principles of these commercial sensors, and the development from our research group. We present potentiometric total NOx sensors that can operate in harsh environments, and impedance-based NH3 sensor for transportation industry. For detecting NO in human breath, we have demonstrated two strategies, the first using a resistive approach, and the second with an array of potentiometric sensors. Data from these sensors, their limitations as well as novel MEMS-based approaches for miniaturization is presented.