Covering: up to December 2021Picrotoxane sesquiterpenoids are a special category of natural products known to have a picrotoxane skeleton and are characterised by a highly oxidised cis-hydrindene core, lactone rings, and epoxide functionalities. Ever since the first picrotoxane was isolated from Menispermum cocculus in the early 19th century, these compounds have long attracted the attention of natural product chemists, synthetic chemists, and pharmacologists for their particular structures and powerful biological activities. This review extensively summarizes a total of 132 naturally occurring picrotoxane sesquiterpenoids, taking into account their distributions, structural classifications, chemical and bio-synthetic researches, and bioactivities. It provides a comprehensive and in-depth perspective for further investigation on picrotoxane sesquiterpenoids.