Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review advances in chemical techniques for the isolation and structural elucidation of natural products that have reduced these technological barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.