Antibiotic innovation has slowed. Despite substantial public investment, research and development (R&D) remains insufficient to address rising antimicrobial resistance (AMR). In this historical review, we draw on quantitative and qualitative historiographic methodologies, as well as on testimony from key stakeholders, to reconstruct antibiotic innovation challenges and public interventions since 1980. Emerging in the 1990s and gaining traction around 2010, the “empty antibiotic pipeline” metaphor, as well as its market failure diagnosis, has played a key role in structuring the global R&D response. This reframing described AMR as an incentives-based innovation challenge, which suited industrial and high-income country interests. However, the introduction of so-called push and pull incentives has so far failed to halt the exit of large developers, sustain diversified R&D ecosystems, or address global access challenges. This article explores challenges and conflicts involved in the implementation of the incentives-based innovation approach alongside the ever-greater subsidies required to stabilise small and medium-sized enterprises (SMEs) and attract larger pharmaceutical companies and investment from financial markets. Several SME bankruptcies since 2019 and the mothballing of novel compounds suggest that this is an unsustainable innovation model. This article also explores whether public interventions have been insufficient or whether there is a deeper problem with the central metaphor structuring global action.