Abstract: The possibility of performing designed transition-metal catalyzed reactions in biological and living contexts can open unprecedented opportunities to interrogate and interfere with biology. However, the task is far from obvious, in part because of the presumed incompatibly between organometallic chemistry and complex aqueous environments.  Nonetheless, in the past decade there has been a steady progress in this research area, and several transition-metal (TM)-catalyzed bioorthogonal and biocompatible reactions have been developed. These reactions encompass a wide range of mechanistic profiles, which are very different from those used by natural metalloenzymes. Herein we present a summary of the latest progress in the field of TM-catalyzed bioorthogonal reactions, with a special focus on those triggered by activation of multiple carbon-carbon bonds.