Bacterial genome sequencing has greatly enhanced our understanding of numerous aspects of evolution and bacterial physiology, but this knowledge has not (yet) led to the entry of any novel antibacterial drugs into the industry pipeline.  Despite significant investment in genomics-based target identification and high throughput screening, success in identifying suitable antibacterial lead molecules for any new target has been extremely limited.  Compared to improving incrementally an antibacterial where an established structure-activity relationships exists, converting these scarce novel leads into development candidates is exceptionally challenging.  Further complicating matters is that initial bioinformatic and genomic analysis used to “validate” a target may not always extrapolate to a broader set of strains from the species or to a range of target species.  Thus investment in genomic approaches and broad target discovery is no longer merited.  Rather, we have found that finding novel chemical structures of highly validated targets and optimizing these structures for drug-like properties is a more promising, if less trendy, route.