Significance The manipulation of proteins in a site-selective manner underpins much of modern protein chemistry. A careful evaluation of selenomethionine benzylation led to the identification of a highly efficient bromobenzyl linker for protein bioconjugation. This selenonium-forming ligation reaction can efficiently link proteins to other complex molecules such as synthetic peptides, polymers, or reactive handles. The selenonium product is sufficiently stable at physiological pH, yet is efficiently cleaved by glutathione at intracellular concentrations. Selenomethionine benzylation is a broadly applicable tool for engineering of complex macromolecules.