Because of their complex geometric and electronic structures, the active sites and cofactors of bioorganometallic enzymes, which are characterized by their metal–carbon bonds, pose a major challenge for computational chemists. However, recent progress in computer technology and theoretical chemistry, along with insights gained from mechanistic, spectroscopic, and X-ray crystallographic studies, have established an excellent foundation for the successful completion of computational studies aimed at elucidating the electronic structures and catalytic cycles of these species. This chapter briefly reviews the most popular computational approaches employed in theoretical studies of bioorganometallic species and summarizes important information obtained from computational studies of (i) the enzymatic formation and cleavage of the Co–C bond of coenzyme B12; (ii) the catalytic cycle of methyl-coenzyme M reductase and its nickel-containing cofactor F430; (iii) the polynuclear active-site clusters of the bifunctional enzyme carbon monoxide dehydrogenase/acetyl-coenzyme A synthase; and (iv) the magnetic properties of the active-site cluster of Fe-only hydrogenases.