Often, the ability to access analogues of natural products for drug discovery and medicinal chemistry is restricted by our limited ability to manipulate natural product biosynthesis in microbes. For example, the large size and staggering complexity of polyketide biosynthesis render the rational redesign and optimization of such pathways for improved yield and generation of analogues difficult, if not impossible in some cases. To address this major limitation, we have created genetically encoded biosensors that produce a fluorescent signal in the presence of the target natural product. These designer biosensors enable ultra-high-throughput approaches to engineering natural product biosynthesis and are being used to screen the productivity of thousands of pathway variants, thereby bypassing our limited ability to rationally reprogram complex biosynthetic pathways.