Recent highlights in the synthesis of polyketide natural products and structural analogs as promising anticancer agents are described, focusing on the halichondrins and eribulin (Eisai), together with recently published research on bryostatin, dictyostatin, spongistatin, peloruside, spirastrellolide, palmerolide, reidispongiolide, spirangien and saliniketals. These examples demonstrate the centrality of bioactive polyketides in current and future anticancer drug discovery, and the increasingly key role of efficient total synthesis in providing a sustainable supply of such compounds for drug development.