Novel psychoactive substances (NPS), especially those newly created, are largely an unknown quantity, particularly in terms of their potential serious adverse effects. This means that policy-makers and clinicians are under-informed about appropriate responses. Collation of detailed information on deaths related to NPS use can help in providing knowledge and understanding these aspects of the NPS phenomenon. The purpose of this review is to outline the role(s) which such evidence-based data can play in this respect. UK NPS-related cases demonstrate differences in definitions used by the General Mortality Registers, and differences between countries, not only in terms of the type of NPS implicated in deaths, but the number and extent of such deaths over time. NPS deaths are continuing to increase numerically and as a proportion of all drug-poisoning deaths. In order to better understand how specific molecules contribute to and/or cause death, detailed information collected by Special Mortality Registers can provide examples of substances' modes of action, adverse effects, symptomatology, treatment interventions, mechanisms of death, etc. This information can provide clinicians and policy-makers with objective information on the serious harms from such emerging molecules. Such evidence-based advice informs public health interventions, service provision and policy decisions on regulation and control of NPS. However, without reliable, accurate and complete information that is correctly collated, scientifically analysed and disseminated in a timely manner, an understanding of the phenomenon of what deaths can be ascribed to NPS, their characteristics and nature will remain unachieved, and thus limit what can be done to reduce them.