jats:titleAbstract</jats:title>jats:pThis review highlights the various challenges overcome during our recent synthetic campaign towards (−)‐leiodermatolide, a potent cytotoxic and antimitotic macrolide isolated from the marine sponge jats:italicLeiodermatium</jats:italic> sp. This structurally unprecedented macrocyclic chemotype represents a promising lead for anticancer drug discovery, provided a sustainable supply can be realised by an efficient chemical synthesis. Faced with the stereochemical ambiguities arising from our structural assignment work, a flexible and modular synthetic strategy was adopted for the construction of various key fragments, as a prelude to the controlled assembly of the two diene moieties. Installation of the nine stereocentres was achieved by the strategic use of boron‐mediated aldol reactions of chiral ketone building blocks. Following the exploratory construction of the macrocyclic core, we revised our strategy to circumvent some problematic steps, enabling a highly convergent total synthesis of (−)‐leiodermatolide.</jats:p>