Antimicrobial resistance is an urgent threat to human health, with the rise in resistant bacteria coupled with a decline in the development of new antibiotics. This talk will present an overview of approaches to discovering both new antibiotics and non-traditional antimicrobial agents. Research projects from our group will be used to illustrate some of these tactics, including a crowdsourcing initiative designed to uncover novel chemical diversity with antimicrobial activity (the Community for Open Antimicrobial Drug Discovery), a ‘rediscovery’ approach focused on a neglected antibiotic initially identified over 50 years ago, and novel approaches based on adding additional functionality to existing antibiotics. Without significant changes in treating drug-resistant infections, we face a return to a pre-antibiotic era where a simple scratch can kill.