Natural product novel psychoactive substances (‘legal highs’) are psychoactive plants or fungi that can be easily acquired from the Internet or retail outlets known as head shops without legal restriction. These materials are either stimulant-, hallucinogenic- or analgesic-like in their effects (or a combination) and many contain phenylethylamine- and tryptamine-derived natural products that are responsible for their pharmacological action. Unfortunately in many cases the chemistry of these materials was studied some time ago and up-to-date chemical and pharmacological analysis of these complex materials is absent, with little understanding of their effects singularly or in combination with other recreational drugs. This chapter covers the chemistry of fungal and herbal novel psychoactive substances and gives an overview of what is currently known of their pharmacology and toxicology. The legality of these materials will vary from country to country and over a period of time as their popularity varies and their adverse effects become better understood.