With the aim of improving the health of individuals and populations, medical schools are transforming curricula to ensure physician competence encompasses health systems science (HSS), which includes population health, health policy, high-value care, interprofessional teamwork, leadership, quality improvement, and patient safety. Large-scale, meaningful integration remains limited, however, and a major challenge in HSS curricular transformation efforts relates to the receptivity and engagement of students, educators, clinicians, scientists, and health system leaders. The authors identify several widely perceived challenges to integrating HSS into medical school curricula, respond to each concern, and provide potential strategies to address these concerns, based on their experiences designing and integrating HSS curricula. They identify two broad categories of concerns: the (1) relevance and importance of learning HSS—including the perception that there is inadequate urgency for change; HSS education is too complex and should occur in later years; early students would not be able to contribute, and the roles already exist; and the science is too nascent—and (2) logistics and practicality of teaching HSS—including limited curricular time, scarcity of faculty educators with expertise, lack of support from accreditation agencies and licensing boards, and unpreparedness of evolving health care systems to partner with schools with HSS curricula. The authors recommend the initiation and continuation of discussions between educators, clinicians, basic science faculty, health system leaders, and accrediting and regulatory bodies about the goals and priorities of medical education, as well as about the need to collaborate on new methods of education to reach these goals.