Twelve years have now passed since the influential WHO Report on the Social Determinants of Health (SDoH) in 2008. A group of senior international public health scholars and decision-makers met in Italy in mid-2019 to review the legacy of the SDoH conceptual framework and its adequacy for the many challenges facing our field as we enter the 2020s. Four major categories of challenges were identified: emerging “exogenous” challenges to global health equity, challenges related to weak policy and practice implementation, more fundamental challenges related to SDoH theory and research, and broader issues around modern research in general. Each of these categories is discussed, and potential solutions offered. We conclude that although the SDoH framework is still a worthy core platform for public health research, policy, and practice, the time is ripe for significant evolution.