Structurally complex polyketide natural products, isolated from a variety of marine and terrestrial sources, continue to provide a valuable source of rewarding targets for the synthetic chemist to tackle. In this account, we provide an overview of the total synthesis of several structurally fascinating polyketides with promising anticancer activity completed in our group based on our versatile asymmetric aldol methodology-spirastrellolide A methyl ester, leiodermatolide, rhizopodin and chivosazole F-and highlight the unanticipated challenges and discoveries encountered.