Lignin is an attractive alternative to fossil fuels as a feedstock for the sustainable manufacture of chemicals. Emergent strategies for lignin valorization include tandem processes whereby thermochemical fractionation of the biomass yields a mixture of lignin-derived aromatic compounds (LDACs), which are then transformed into target compounds by a microbial cell factory. Identifying LDAC-degrading pathways is critical to optimize carbon yield from diverse depolymerization mixtures. Characterizing enzymes - especially those that catalyze the rate-limiting steps of O-demethylation, hydroxylation, and decarboxylation - informs and enables biocatalyst design. Rational, structure-based engineering of key enzymes, as well as untargeted, evolution-based approaches, further optimize biocatalysis. In this review we outline recent advances in these fields which are critical in developing biocatalysts to efficiently synthesize lignin-based bioproducts.