This paper aims at sharing some lessons learned by practitioners and researchers in terms of risk regulation when facing uncertainties and ambiguities inherent and induced by the occurrence and the management of major risks, either technological, natural or health diseases. On one hand, we have noticed that there are significant differences when analyzing the several frameworks in these domains, either from risk regulations (risk averse approach) and from business point of view (risk taking approach). On the other hand, we have observed how scientific segmentation of problems can increase blindness or some blind spots which can weaken major risks prevention policies. The paper is structured as following. - We will first discuss some key aspects of public risk regulation focusing on how an analytical framework to assess the “quality” of decision process can contribute to a more sustainable major risks’ governance. - We will then describe the different types of risk regulation situations based on real case studies analysis (ex. Air pollution). - We will finally present what we means by “quality of decision process” and conclude by suggesting some key challenges for risk and policy analysts.