Planar chirality, resulting from a lack of symmetry with respect to a plane, can arise when substituents on a macrocycle are locked and unable to rotate. Such conformations can be critical for the biological activity of a compound but are difficult to control during synthesis. As enzymes are often naturally stereoselective, Gagnon et al. turned to biocatalysis as an approach for making planar chiral macrocycles. Using the serine hydrolase Candida antarctica lipase B (CALB), the authors demonstrated the ability to make macrocyclic paracyclophane rings of various sizes from aromatic diols and diacid aliphatic linkers. The reaction was also amenable both to certain alternative linkers containing a rigid diyne moiety or a disulfide bridge and to additional substituents on the aromatic ring without compromising enantioselectivity. The incorporation of reactive handles such as halogens or alkyne groups on the aromatic ring thus provided the capability for further functionalization and diversification beyond the tolerance of the CALB enzyme. This chemoenzymatic approach to macrocycle synthesis provides a more environmentally friendly and stereoselective route to potentially useful new compounds.