Decentralization and regionalization are strategic themes for reforms in the health system. This paper analyzes the complex process of health regionalization being developed in Brazil. This paper identifies that the normative framework from the Brazilian National Health System, SUS has made advances with respect to its institutionalization and overcoming the initial centrality involved in municipalization. This has strengthened the development of regionalization and the intergovernmental agreement on health but the evidence points to the need to promote a revision. Based on document analysis, literature review and the views given by the authors involved in management in SUS as well as generating radically different views, the challenges for the construction of a regionalization that is active, is debated. We also discuss: its relations with planning and the dimensioning of service networks, the production of active care networks and shared management spaces, the inter-federative agreements and regional regulations, the capacity to coordinate regional systems and financing and the impact of the political dimension and electoral cycles. Regionalization (and SUS itself) is an open book, therefore ways and possibilities on how to maintain an active form of regionalization can be recommended.