After being pushed into the background of the academic discussion on the evolution of the post-bipolar international politics, the debate over the role of nuclear weapons and the effects of their proliferation has partially revived in the recent months, following the signing of the agreement with Iran and the armed confrontation in the eastern regions of Ukraine. This article reviews the most prominent scholarly contributions on classical nuclear deterrence theory and sheds light on the new challenges of nuclear proliferation in contemporary international politics. In the post-global international system the old central axis of the system has been substituted by less stable relations both at global and regional levels. Today state and non-state actors involved in nuclear relations belong to different ‘civilizations’, and the traditional deterrence exercised by states toward non-state actors may be totally ineffective, given that de-territorialised and transnational terrorist organizations are impermeable to conventional nuclear threats. In this complex environment, the nuclear non-proliferation regime created during the Cold War looks manifestly inadequate to face the new challenges, and its main pillar, the NPT, is subject to many pressures that could lead to its collapse.