Harnessing the power of transition metal catalysis in biological settings, and especially inside living cells, can open a world of new opportunities in chemical and cell biology, as well as in biomedicine. Yet, advancing in this endeavor requires to address major challenges associated to biocompatibility, transport and bioorthogonality issues, as well as the stability of the catalyst in these aqueous, crowded environments. This is especially relevant in reactions that involve the formation of organometallic intermediates that are considered labile, such as metal carbenes. Here, we demonstrate the viability of performing catalytic metal carbene intermolecular transfer reactions inside live mammalian cells. In particular, we show that copper (II) catalysts can promote the intracellular annulation of alpha-keto diazocarbenes with ortho-amino arylamines, in a process that is initiated by the insertion of the carbene into the N-H bond of the substrate. The potential of this transformation is underscored by the intracellular synthesis of a product that alters mitochondrial functions, and by demonstrating cell selective biological 2 responses using targeted copper catalysts. Considering the wide reactivity spectrum of metal carbenes, this work opens the door for significantly expanding the repertoire of reactions that can be performed in live environments and for unveiling new biological applications.Live cells can be viewed as microfactories that perform thousands of simultaneous chemical reactions in a highly regulated manner. Most of these reactions are promoted by enzymes, proteins that have evolved to exhibit exquisite rates and selectivities. 1-2 Over one-third of the enzymes feature metals at their active sites, and therefore are coined as metalloenzymes. In recent years, there has been an impressive progress in the creation of laboratory versions of metalloenzymes that catalyze "new-to-nature" reactions. [3][4][5][6][7][8][9] However, the application of these catalytic metalloproteins has been essentially restricted to the realm of synthetic methodology. Their use for biological purposes, in the natural environments of enzymes (living cells or organisms), is more challenging, and remains to be uncovered. [10][11][12][13] An alternative approach to perform artificial chemical reactions in live cells has recently emerged, and consists of the use of exogenous, discrete transition metal catalysts. [14][15][16][17][18][19] While the catalytic activity of these reagents is far away from that of metalloenzymes, they can permeate living cells, and eventually trigger non-native organometallic reactions. Therefore, several transition-metal reagents that mediate intracellular allylic or propargylic deprotections, 20-27 cyclizations, 28-29 cross couplings, [30][31][32][33] or even formal cycloadditions, [34][35][36][37][38] have been recently disclosed. However, the portfolio of reactions is yet too small, especially when compared with the enormous breadth and potential that organometallic catalysts exhibit in organic solve...