Natural products (NPs) are central to the history and landscape of new molecular entities (NMEs) for human medicinal agents. A rigorous assessment of all FDA-approved NMEs reveals that NPs and their derivatives represent over 50% of currently marketed drugs. However, their representation has diminished over the past two decades, in part because of technical hurdles associated with screening of natural products in high-throughput assays against molecular targets, and the reoccurrence of previously reported metabolites in follow-up processes. Here, I present innovative, state-of-the-art strategies for discovery of NMEs and describe the recent technical advances that have significantly reduced the barriers to discovery of NMEs. I will also assess the use of new genomic-based approaches to augment traditional strategies for studying NPs using a case study from my research in antimicrobial drug discovery.