The 2015 National Security Strategy identifies the proliferation and/or use of weapons of mass destruction (WMD) among the top strategic risks to the Nation’s interests. This paper examines four pressing WMD challenges for the next U.S. administration. First, the prospects of a direct clash between the United States and a nuclear-armed adversary that could escalate to the nuclear level are likely to grow. Russia in particular has become more assertive in challenging U.S. interests and has developed concepts for the limited use of nuclear weapons in a conflict with the North Atlantic Treaty Organization (NATO). Second, the scope of North Korea’s nuclear, chemical, and suspected biological weapons programs likely will require resources for countering WMD that exceed those currently available to the United States and South Korea. Third, longstanding international efforts to prohibit chemical and biological weapons are threatened by the reemergence of chemical weapons use and potentially by rapid advances in the life sciences. Finally, concern that the 2015 Joint Comprehensive Plan of Action may only postpone—rather than prevent—Iran’s acquisition of nuclear weapons will perpetuate tensions and proliferation pressures in the region. To meet these challenges, the next U.S. administration needs to: close gaps in capabilities, plans, and policies that weaken deterrence; reduce incentives for further proliferation by enhancing monitoring and verification measures and reassuring allies and partners; strengthen the Nation’s countering-WMD posture with increased resources and improved organization; stay on top of and leverage rapid scientific and technological developments in the life sciences and related fields; and improve the education of military officers, civilian national security professionals, and the broader public on WMD challenges and the necessary responses thereto.