Contrast-enhanced mammography (CEM) has emerged as a high-performance diagnostic tool, showing comparable accuracy to breast magnetic resonance imaging. However, a clinical-regulatory gap persists: although international guidelines increasingly support CEM, most iodinated contrast agents used for CEM may lack product-specific regulatory approval for breast imaging applications in certain jurisdictions; their use in those settings is therefore off-label. This commentary explores the medico-legal implications of this discrepancy, emphasizing the necessity of rigorous clinical protocols, enhanced informed consent, and institutional governance. Rather than proposing ready-to-use operational documents applicable in all jurisdictions, the manuscript outlines the essential elements that should be incorporated into standardized safety pathways and dedicated informed consent procedures to support risk management and medico-legal compliance. By integrating current clinical evidence—including the RACER trial—with ethical and legal considerations, this commentary proposes a practice-oriented medico-legal framework that may assist institutions in developing jurisdiction-specific protocols for the safe implementation of CEM. The adoption of CEM as an increasingly evidence-supported imaging technique should therefore be accompanied by appropriate regulatory awareness, explicit informed consent, and standardized institutional procedures.