Background:There is an increasing awareness of the multiple potential pathways leading to human health risks from hydraulic fracturing. Setback distances are a legislative method to mitigate potential risks.Objectives:We attempted to determine whether legal setback distances between well-pad sites and the public are adequate in three shale plays.Methods:We reviewed geography, current statutes and regulations, evacuations, thermal modeling, air pollution studies, and vapor cloud modeling within the Marcellus, Barnett, and Niobrara Shale Plays.Discussion:The evidence suggests that presently utilized setbacks may leave the public vulnerable to explosions, radiant heat, toxic gas clouds, and air pollution from hydraulic fracturing activities.Conclusions:Our results suggest that setbacks may not be sufficient to reduce potential threats to human health in areas where hydraulic fracturing occurs. It is more likely that a combination of reasonable setbacks with controls for other sources of pollution associated with the process will be required.Citation:Haley M, McCawley M, Epstein AC, Arrington B, Bjerke EF. 2016. Adequacy of current state setbacks for directional high-volume hydraulic fracturing in the Marcellus, Barnett, and Niobrara Shale Plays. Environ Health Perspect 124:1323–1333; http://dx.doi.org/10.1289/ehp.1510547