As apparent from the examples outlined in this review, enzymes are exquisite catalysts for the selective introduction of chirality and complexity in natural product synthesis. Inspired by nature, naturally occurring biosynthetic enzymes are currently not only used at single strategic steps of total syntheses but are also combined in complex cascades to mimic biosynthetic pathways in vitro. Moreover, chemoenzymatic cascades have already made an entrance into the pharmaceutical industry for the synthesis of active pharmaceutical ingredients from commodity chemicals, as their application can shorten development routes significantly and/or avoid unwanted side reactions and toxic wastes. In this respect, protein engineering of naturally occurring enzymes is a powerful tool to tailor their reactivities and selectivities to match the desired application. We are convinced that in the future we will see more and more applications of such specifically engineered enzymes in natural product synthesis, as this will allow access to a wider range of natural product derivatives as well as the design of "new-to-nature" biosynthetic pathways.