The process of risk regulation is crucial across a range of institutions, sectors and industries. Regulatory bodies worldwide are confronted with a plethora of challenges in managing risks and uncertainties. The precise sources of these challenges are diverse, but are commonly associated with the degree of confidence in predicting and quantifying risks. When the level of confidence is high, regulators tend to specify the outputs and take quantitatively informed preventive measures. However, when levels of confidence are lower, regulators may favour an inflection toward more qualitative considerations of risks to inform resilience building and absorption of adverse consequences. As part of an ongoing research project designed to explore the potentialities of developing a holistic framework for risk assessment which blends qualitative and quantitative methods, this article maps out the key challenges involved in evaluation and decision-making within risk regulatory bodies. In defining the problems and issues faced both by organizations in general and practitioners involved in everyday assessment and management of risk, we have developed a heuristic designed to assist in understanding, categorising and evaluating risk. It is anticipated that the development of knowledge in this area can contribute toward progressive process modifications, improved decision-making at senior management level, and enhance risk management practices amongst regulatory agencies. The project involved semi-structured interviews with practitioners working in risk regulatory bodies from the UK, Germany, France, Belgium, the Netherlands and New Zealand. In coalescing the findings of empirical studies, the sources of these challenges were discussed as being related to rational, technical and expert factors. The main areas of analysis focused on in this article revolve around the process of evaluation, organisational strategies, structural factors and expert perceptions.