Human epidermal growth factor receptor 2 (HER2) was acknowledged as an important therapeutic target in breast cancer more than 25 years ago. Subsequently, significant basic science and translational discoveries have resulted in the approval of four HER2-targeted therapies over the past 15 years. This editorial discusses future challenges regarding selection and development of treatments for HER2-positive breast cancer, which can only be met by continuing to support research efforts into the basic mechanisms by which cancer cells escape targeted therapies. Identifying specific molecular mechanisms underlying the sensitivity or resistance to each HER2-targeted agent will ultimately allow individualized therapy for each patient.