Natural product biosynthesis is nature's tinkering ground for developing new enzymes that can achieve chemical transformations that are outside the purview of traditional chemical catalysis. Herein we describe a genome mining approach that leads to the discovery of a halogenase that regioselectively brominates a tryptophan side chain indole for a macrocyclic peptide substrate, enabling downstream chemical arylation by Suzuki-Miyaura coupling. The halogenase was found to prefer a macrocyclic peptide substrate over a linear peptide. The brominase presents a starting point for biocatalytic access to macrocyclic peptides bearing a chemically versatile aryl-bromide reactive handle.