Hemicalide is a marine natural product isolated from the sponge H emimycale sp ., collected near the Torres Islands of Vanuatu. It is characterized by cytotoxicity in the sub-nanomolar range, with an original mode of action. This article describes the establishment of the flat structure of hemicalide, based on extensive use of 2D-NMR experiments. The molecule belongs to the polyketide class with an irregular combination of acetates and propionates and adorned with two unusual hydroxylated six-membered ring lactones. After publication of the original patent, groups in Paris and Cambridge (UK) launched synthetic programmes with the aim of elucidating the configurations of some of the 21 stereogenic centres. The second part of the article discusses these achievements and presents the best hypothesis, to date, for hemicalide.