Identification of new antibiotics remains a huge challenge. The last antibiotic of new chemical class and mechanism was discovered more than 30 years ago. Advances since have been largely incremental modifications to a limited number of chemical scaffolds. Discovering and developing truly new antibiotics is challenging: the science is complex, and the development process is time consuming and expensive. Herein, we focus on the discovery phase of modern antibacterial research and development. We argue that antibacterial discovery has been challenged by a poor understanding of bacterial permeability, by generic in vitro conventions that ignore the host, and by the inherent complexity of bacterial systems. Together, these factors have colluded to challenge modern, industrial, and reductionist approaches to antibiotic discovery. Nevertheless, advances in our understanding of many of these obstacles, including a new appreciation for the complexity of both host and pathogen biology, bode well for future efforts.