One-fifth of the way through the 21st century, a commonality of factors with those of the last 50 years may offer the opportunity to address unfinished business and current challenges. The recommendations include: (1) Resisting the tendency to oversimplify scientific assessments by reliance on single disciplines in lieu of clear weight-of-evidence expressions, and on single quantitative point estimates of health protective values for policy decisions; (2) Improving the separation of science and judgment in risk assessment through the use of clear expressions of the range of judgments that bracket protective quantitative levels for public health protection; (3) Use of comparative risk to achieve the greatest gains in health and the environment; and (4) Where applicable, reversal of the risk assessment and risk management steps to facilitate timely and substantive improvements in public health and the environment. Lessons learned and improvements in the risk assessment process are applied to the unprecedented challenges of the 21st century such as, pandemics and climate change. The beneficial application of the risk assessment and risk management paradigm to ensure timely research with consistency and transparency of assessments is presented. Institutions with mandated stability and leadership roles at the national and international levels are essential to ensure timely interdisciplinary scientific assessment at the interface with public policy as a basis for organized policy decisions, to meet time sensitive goals, and to inform the public.