The unique 16-membered macrolide (+)-exiguolide (1) was the target of a total synthesis featuring radical and Prins cyclizations of β-alkoxyacrylates, along with ring-closing olefin metathesis. The structure incorporates two cis-2,6-disubstituted oxane rings where one of the rings has an exocyclic enoate group. The successful synthesis of 1, isolated from a marine sponge, led to the unambiguous determination of its absolute stereochemistry.