Amphidinolides C, F, and U, including C2‐C4 analogs, are highly cytotoxic marine macrolides, mainly isolated from dinoflagellates of the genus Amphidinium . All these polyketides share a 75 % or more similar structure, highlighted by a macrolactone ring, at least one trans ‐2,5‐substituted‐THF motif and a characteristic polyenic side chain. From their isolation and absolute configurational assignment, the total synthesis of these marine macrolides represented an intense challenge to the organic synthesis community over the last 15 years, with around 14 research groups engaged in this inspiring task. In the first part of this review, we present the different approaches to the isolation and characterization of these natural products, including the most recent analogs, which may cast doubt on the biogenetic origin of these compounds. The various synthetic approaches to the total synthesis of C, F, and U amphidinolides are presented in a second part, focusing on key reactions and/or innovative strategies. The review concludes in a third section summarizing the successful approaches leading to the total synthesis of one of the members of this amphidinolide subfamily.