The new psychoactive substances (NPS) phenomenon has emerged as a global threat that challenges public health and institutions. There are important qualitative differences between the NPS and traditional drugs phenomena. We discuss these differences and explore the complex structure of the NPS phenomenon. We analyse the entire phenomenon with a global, holistic approach. We present an original framework to help policy makers, healthcare practitioners, and community workers understand the NPS phenomenon's structure and to plan comprehensive policy responses and prevention strategies. We discuss fundamental characteristics, driving forces, routes of information, and social and individual health risks of the phenomenon. We conclude that a holistic approach integrating all aspects of the framework is essential for addressing this emerging threat. We give practical examples of interventions likely to be effective.