In the Introduction to this volume, we stressed the increasing discrepancy between the central, persistent problems in the health domain and its incumbent regime (structures, cultures and practices). We argued that this regime was shaped by the typically modern, conventional biomedical paradigm, in which health and disease are (virtually exclusively) located in the (universal) body, and may be controlled by professional intervention with little room for patient agency. From that modernization theoretical perspective (Grin, 2010: 228–231; 2012) the persistence of three major contemporary challenges to health systems may be understood in different ways: problems with affordability, quality, acceptability and accessibility result from following this paradigmatic orientation too long and too exclusively; the difficulties of dealing with non-communicable diseases arise as they have more complex pathologies, located not merely in the body but in (interactions among) bodily processes, life practices, life conditions and patient agency; and the increasing care demand, associated with aging, which often involves non-communicable diseases (NCDs), is difficult to meet until this is taken into account. Meeting these challenges requires appreciation of the limits of the classical paradigm, moving to a more integral orientation on health and disease. Current attempts to reach what we called a “sustainable” health system – transcending existing shortcomings regarding, and tensions between, affordability, quality, acceptability and accessibility of care – often fail because they largely neglect these elements, as explicitly demonstrated by Van Raak and De Haan (Chapter 3). In this final chapter, we seek to articulate what we have learned from the preceding chapters on the “why and how” of the persistence of contemporary challenges, as well as on opportunities and problems implied by contemporary experimental practices that might contribute to a more sustainable healthcare.