During the last two decades, marine organisms such as sponges, tunicates, softcoral and starfish proved to be productive sources of structurally complex metabolites presenting unprecedented architectures. These marine natural products often display unexpected biological properties that make them potential candidates for therapeutic applications. Among these fascinating molecules, the polyketide macrolides having a macrolactone as key structural feature represent an important class of biologically active compounds. Many congeners of this family are potent cancer cell growth inhibitors and thus appears to represent promising leads for the development of new anti-cancer agents. Nevertheless, a limitation to their implementation in clinical evaluation is related to their low natural abundance, which is stimulating organic chemists to invent efficient synthetic routes to address this supply issue. In 1993, the research groups of Pettit, Kitagawa/Kobayashi and Fusetani independently reported the isolation, from marine sponges, of a family of related highly oxygenated macrolactones containing highly substituted 6,6-spiroketals and tetrahydropyran rings. These molecules were found to be among the most potent cancer cells growth inhibitors tested to date by the U.S. National Cancer Institute on a panel of 60 human carcinoma cell lines, with GI50 values in the nanomolar and picomolar ranges. Despite these promising properties, further biological investigations were precluded by the extremely low quantities that can be obtained by extraction of marine organisms and the unacceptable ecological impact of larger scale isolation of the producing sponges. This scarce abundance, combined with remarkable structural complexity, prompted many research groups to address the challenge of the synthesis of these macrolides. We give here an overview of the biological properties of spongistatins and related structures and of the different pathways that have been developed for their total syntheses and the synthesis of key-subunits.