Medical education is at a crossroads. Facing challenges wrought by science and technology as well as societal change, the curriculum is increasingly out of synch with new needs in teaching content and medical practice. The path to significant curricular reform is difficult because of a variety of factors, including deeply entrenched values, the natural resistance to change, and the accreditation process. Indeed, even the very definition of what it means to be a professional is changing with profound implications for the future role of the physician and the sacrosanct doctor-patient relationship.In this Invited Commentary, the author enumerates challenges facing medical education in the current era. To address these challenges, the author recommends specific curricular emphases for 21st-century medical education: knowledge capture and curation, collaboration with and management of artificial intelligence applications, a deep understanding of probabilistic reasoning, and the cultivation of empathy and compassion in accordance with ethical standards. Given these needs, it is imperative that schools act today to undertake significant curricular reform and, in so doing, strive to make the hard changes necessary to produce optimal practitioners in a rapidly transforming 21st century. The author provides first steps an institution can take to begin to address these challenges.