The development of highly sensitive and miniaturized sensors that capable of real-time analytes detection is highly desirable. Nowadays, toxic or colorless gas detection, air pollution monitoring, harmful chemical, pressure, strain, humidity, and temperature sensors based on photonic crystal fiber (PCF) are increasing rapidly due to its compact structure, fast response, and efficient light-controlling capabilities. The propagating light through the PCF can be controlled by varying the structural parameters and core–cladding materials; as a result, evanescent field can be enhanced significantly which is the main component of the PCF-based gas/chemical sensors. The aim of this chapter is to (1) describe the principle operation of PCF-based gas/chemical sensors, (2) discuss the important PCF properties for optical sensors, (3) extensively discuss the different types of microstructured optical fiber-based gas/chemical sensors, (4) study the effects of different core–cladding shapes, and fiber background materials on sensing performance, and (5) highlight the main challenges of PCF-based gas/chemical sensors and possible solutions.