It has become clear that infectious diseases are among the greatest threats to human health and global stability. Chief among these threats is the rise in antibiotic resistance, which endangers our ability to treat otherwise curable infection. The capacity to discover and develop novel agents to fill the pipeline as existing antibiotics are lost to increasing resistance has to date been limited. The goal of this Keystone Symposia conference is to present cutting-edge approaches to antibiotic discovery, including application of expanded chemical space, systems chemical biology, and artificial intelligence; and novel strategies for treating resistant infection, including CRISPR, vaccines, antibodies, phages and conjugates. The promise, challenges, and development paths of these new approaches and strategies will be discussed in the context of lessons learned from prior antibiotic development programs, and new innovations in clinical and regulatory pathways. Additionally, this conference will be held jointly with “The Human Microbiome: Ecology and Evolution.” This pairing will help to facilitate exploration of the impact of antibiotics on the microbiome and the microbiome on antibiotic resistance.