Most antibody diversity occurs in the heavy-chain complementarity determining region 3 (CDR3), which comprises rearranged variable (V), diversity (D) and joining (J) gene segments. Humans and other vertebrates encode a large number of V, D and J gene segments and use V(D)J recombination to generate antibody diversity. By contrast, bovine antibodies are generated from a very limited V gene repertoire. Bovine antibodies are also unusual in that they have exceptionally long heavy-chain CDR3 regions that contain multiple cysteine residues. Wang et al. used deep sequencing analysis to show that bovine antibodies are generated through V(D)J recombination events and mutational mechanisms that promote the conversion of D residues in the CDR3 region to cysteine residues. These cysteine residues faciliate disulphide-bonding events that create unique 'microfolds' in the CDR3 region, and bovine antibodies form an unusual structure comprising a β-strand 'stalk' domain and a disulphide-bonded 'knob' domain. Such unique antibodies may bind antigenic targets that are difficult for traditional antibodies to access, such as channels and pores.