Many mentoring relationships do not reach fruition because the individuals fail to bridge a critical difference. When a difference prevents a learning partnership from achieving its potential, the loss is multidimensional for the individuals and the institution—wasting opportunities for the fostering of current and future talent. Insights into when such impasses are likely to arise may help both mentors and mentees address what feels “undiscussable.” The authors offer numerous examples of how differences related to ethnicity, language, gender, and generation may interfere with the development of mentoring relationships. Next, the authors offer recommendations on preparing for and handling difficult conversations, including creating safety, noticing assumptions and emotions, and raising sensitive issues. Virtually all faculty can become more effective at communicating across differences and addressing difficulties that prevent mentoring relationships from achieving their potential. The pay-offs for these efforts are indisputable: increased effect in the limited time available for mentoring, an expanded legacy of positive influence, and enhanced communication and leadership skills. The honing of these relational skills enhances the colleagueship and teamwork on which virtually all research, clinical, and educational enterprises depend. Academic health centers that systematically support mentoring enhance institutional stability, talent development, and leadership capacity.