The iterative type I polyketide synthases (IPKSs) are central to the biosynthesis of an enormously diverse array of natural products in fungi. These natural products, known as polyketides, exhibit a wide range of biological activities and include clinically important drugs as well as undesirable toxins. The PKSs synthesize these structurally diverse polyketides via a series of decarboxylative condensations of malonyl-CoA extender units and β-keto modifications in a highly programmed manner. Significant progress has been made over the past few years in understanding the biosynthetic mechanism and programming of fungal PKSs. The continuously expanding fungal genome sequence data have sparked genome-directed discoveries of new fungal PKSs and associated products. The increasing number of fungal PKSs that have been linked to their products along with in-depth biochemical and structural characterizations of these large enzymes have remarkably improved our knowledge on the molecular basis for polyketide structural diversity in fungi. This Perspective highlights the recent advances and examines how the newly expanded paradigm has contributed to our ability to link fungal PKS genes to chemical structures and vice versa. The knowledge will help us navigate through the logarithmically expanding seas of genomic information for polyketide compound discovery and provided opportunities to reprogram these megasynthases to generate new chemical entities.