Nature has produced a diverse range of oxygenases for the modification of secondary metabolites with selectivity profiles that are unmatched by conventional man-made catalysts. In the past two decades, organic chemists have begun to harness the synthetic potential of these biocatalysts to develop efficient chemoenzymatic synthesis of complex natural products. Judicious combination of synthetic and enzymatic transformations in multistep synthesis can often result in powerful disconnections that compare favorably with contemporary chemical strategies for accessing the target natural products, while at the same time presenting opportunities to innovate. This Perspective highlights strategic applications of enzymatic hydroxylation to simplify problems in natural product synthesis. Finally, newly discovered enzymes that would facilitate further developments in this field are discussed.