Fungal tetraketide pyrones possess important and potent bioactivities, but their detailed biosynthetic pathways are unknown and synthetic routes to their production are lengthy. Here we investigated the fungal pathways to the multiforisins and compounds related to islandic acid. Heterologous expression experiments yield high titres of these compounds and pathway intermediates. The results both elucidate the pathway and offer a platform for the total biosynthesis of this class of metabolites.