Natural products are a rich source of bioactive compounds that have been used successfully in the areas of human health from infectious disease to cancer; however, traditional fermentation-based screening has provided diminishing returns over the last 20-30 years. Solutions to the unmet need of resistant bacterial infection are critically required. Technological advances in high-throughput genomic sequencing, coupled with ever-decreasing cost, are now presenting a unique opportunity for the reinvigoration of natural product discovery. Bioinformatic methods can predict the propensity of a microbial strain to produce molecules with novel chemical structures that could have new mechanisms of action in bacterial growth inhibition. This review highlights how this potential can be harnessed; with a focus on engineering the expression of silent biosynthetic gene clusters predicted to encode novel antibiotics.