This chapter looks at ‘club drugs’ and novel psychoactive substances (NPSs; previously known as ‘legal highs’). It examines the acute and chronic adverse health effects of these drugs and focuses in particular on their effects on mental health, including their dependence liability and associated withdrawal symptoms. The chapter is based on the best available research evidence on NPSs, which is currently limited, but nonetheless broadly consistent. It also provides practical patient case studies to illustrate key clinical points. Overall, the evidence suggests that interventions aimed at NPSs must be based on the guiding principles and national guidelines used for the management of substance misuse in general. However, NPSs pose a number of additional challenges, which are highlighted in this chapter. This chapter also establishes a conceptual framework for NPSs, which is crucial in helping clinicians to navigate the hundreds of new substances detected in recent years while allowing them to drawn on their existing experience of substance misuse.