This paper addresses policy issues related to uncertainty in earthquake risk in the New Madrid seismic zone and similar environments. I evaluate various sources of data and policy implications related to earthquake hazard, vulnerability, and risk (economic and life-safety consequences). Findings support my belief that, despite the significant uncertainties, opportunities exist to address earthquake risk through properly focused policy. These include: (1) assigning high priority to disaster-response emergency services that also address more routine life-safety risks; (2) focusing life-safety mitigation efforts on the most threatening conditions, such as unreinforced masonry construction; (3) ensuring that mitigation of potential economic loss is strengthened by policy that encourages and does not interfere with a competitive and affordable insurance market based on risk-consistent rates; and (4) requiring that public awareness efforts include realistic information on what is known and not known about the hazard to promote a rational basis for individual decision-making and public policy debate. I also show how proper qualification of “lessons learned” from past earthquakes can improve understanding of policy needs and potential impacts.