Histidine (His) is an ubiquitous ligand in the active site of metalloenzymes that is assumed by default to bind the metal center through one of its nitrogen atoms. However, protonation of His, which is likely to occur in locally slightly acidic environment, gives imidazolium sites that can bind a metal in a carbene-type structure as found in N-heterocyclic carbene complexes. Such carbene bonding has a dramatic effect on the properties of the metal center and may provide a rational for the mode of action of metalloenzymes that are still lacking a solid understanding. Up to now, the possibility of carbene bonding has been completely overlooked. Hence, any evidence for such His coordination via carbon will induce a shift of paradigm in classical peptide chemistry and will be directly included in basic textbooks. Moreover, this unprecedented bonding mode will provide access to unique and hitherto unknown reactivity patterns for artificial enzyme mimics. Undoubtedly, such a break-through will set a new stage in modern metalloenzyme research. A multicentered approach is proposed to identify for the first time carbene bonding in enzymes. This approach unconventionally combines the current frontiers of organometallic and biochemical knowledge and hence crosses traditional boarders. Specifically, we aim at probing carbene bonding of His by identifying reactivity patterns that are selective for metal-carbenes but not for metal-imine complexes. This will allow for efficient screening of large classes of metalloenzymes. In parallel, active site models will be constructed in which the His ligand is substituted by a heterocyclic carbene as a rigidly C-bonding His analog. For this purpose chemical synthesis will be considered as well as enzyme mutagenesis and subsequent carbene coordination. While such new bioorganometallic entities will be highly attractive to probe the influence of C-bound His on the metal site, they also provide conceputally new types of versatile catalysts.