Over the past 4 billion years or so, beginning in the primordial soup from which terrestrial life descends, Mother Nature has been molding matter into a seemingly endless number of combinations and searching among them for useful properties. Almost certainly, the vast majority of these atomic combinations have held little value to Her but every so often, a particular combination is found, a gem of perfect dimension or reactivity possessing an extraordinary quality. The quality imparts a value to this particular arrangement of matter and because of it the combination is allowed to persist along with all the other extraordinary combinations. Humanity has long coveted Mother Nature’s process and aspired to emulate Her. Counted among Nature’s wondrous creations are the polyketides and the eponymous polyketide synthase enzymes that assemble them. As a class of natural products, polyketides display incredible properties and have found wide-spread use in society as antibiotics, cholesterol medications and cancer therapeutics. The enzymatic molecular machines that biosynthesize these miracles are just as impressive and are regarded with envy by human chemists for their ability to make sophisticated chemical agents with unrivaled precision under the mildest of conditions. This work aims to inch forward our understanding of these exquisite assembly lines so that we may better understand and imitate Nature.