C-H activation has emerged as a viable alternative to traditional C-C bond forming reactions such as the Suzuki-Miyaura, Stille, Negishi and others. However, C-H activation is rarely employed in total synthesis or fine chemical manufacture, particularly as an end-game strategy. This may be due to the harsh conditions typically required. For C-H activation to become a truly useful and versatile methodology, conditions must emerge which are applicable to compounds with multiple functionalities. In this review, we hope to inspire the chemistry community to focus their efforts on milder conditions for C-H activation and cross-dehydrogenative coupling. To this end, we have focused on describing C-H activation as it has been applied to several classes of biologically interesting, but chemically sensitive motifs: the 2-pyrones, 2-pyridones, 2-coumarins and 2-quinolones.