Antibiotics have been a key component of modern medicine for decades. A critical question is why not enough antibacterials are being developed to tackle the growing challenge of drug-resistant infections. While current innovation in the early preclinical pipeline is encouraging, the journey for any new antibiotic is burdened with multiple challenges across its early and late development path. In this viewpoint, we explore the barriers to antibiotic development and how the Wellcome Trust is addressing these problems and working toward developing long-term solutions to facilitate a sustainable R&D ecosystem.