As the states parties to the nuclear Non-Proliferation Treaty (NPT) plan for the May 2010 review conference, they are faced with recurring political challenges that call into question the long-term sustainability of the presently constituted non-proliferation regime, notwithstanding the important role the NPT and its related institutions have played in slowing the pace of proliferation for four decades. Even if the review conference is deemed a success, its outcome is unlikely to address the regime's core structural weaknesses and normative contradictions. Frustration with the continuing status and benefits accorded to nuclear-armed states outside as well as within the NPT, will continue to diminish confidence in the effectiveness of traditional non-proliferation and deterrence practices. The progressive reframing of security in terms of creating a world without nuclear weapons may be little more than rhetoric for some leaders, but it has widespread public support. A growing number of governments are now expressing interest in new approaches and steps, including consideration of a nuclear weapons convention as a practical objective to work towards. The article discusses the challenges and options for the non-proliferation regime and concludes that efforts to halt future proliferation will increasingly focus on reshaping the norms and rules to pave the way for negotiating a new nuclear security compact, based on a verified process to prohibit and eliminate the possession as well as the use of nuclear weapons.