Carbon–carbon (C–C) bonds make up the skeletons of most organic molecules. The selective manipulation of C–C bonds offers a direct approach to editing molecular scaffolds but remains challenging. The kinetic inertness of C–C bonds can be overcome with transition-metal catalysis, which, nevertheless, relies on a substrate being highly strained or bearing a permanent directing group (DG). The driving force for C–C activation in these cases is strain relief and the formation of a stable metallocycle, respectively. Over the past two decades, a strategy has emerged that uses temporary or removable DGs to effect C–C activation of more common and less strained compounds. A variety of C–C bonds in less strained organic molecules are converted into more reactive transition-metal–carbon (M–C) bonds, enabling downstream transformations as part of diverse synthetic methods. This Review highlights catalytic approaches using temporary or removable DGs to help activate unstrained C–C bonds. The content is organized according to the temporary or removable nature of the DGs and includes applications in the synthesis of natural products or bioactive molecules.