This review will focus on selected applications of Sonogashira coupling and subsequent transformations as key steps in the total synthesis of natural products. A brief introduction to the history and development of Sonogashira coupling will be presented. The organization of the synthetic applications is based on the structure of target molecules and the transformations followed by the Sonogashira coupling, which includes (1) preparation of natural products containing conjugated enynes or enediynes; (2) Sonogashira coupling followed by stereoselective reduction and (3) Sonogashira coupling followed by regioselective annulations.