Antibody-drug conjugates (ADCs) are redefining treatment options for advanced breast cancer, demonstrating efficacy across all subtypes. However, their rapid clinical expansion has brought several outstanding challenges. These include the need for rational treatment sequencing strategies. Another challenge is the appropriate and ethical design of clinical trials. The tolerability of drugs by patients is also a problem. A limitation is the mononational development programs of the ADC. Authors Giulia Notini, Giampaolo Bianchini, José Manuel Perez-Garcia and Javier Cortés discuss these challenges in perspective. The rapid advancement of ADCs is outpacing the current clinical strategy.