Polyketide natural products are biosynthesized by four basic strategies. The least understood among these are the iterative Type I fungal polyketide synthases (IPKSs). Termed “iterative,” these comparatively simple multidomainal proteins exemplify the rare and impressive catalytic ability to reuse active sites multiple times to process intermediates of increasing size without their release. They can be partially reducing or fully non-reducing. The latter are classically imagined to form poly-b-keto intermediates that grow to a given chain length, which is stabilized and templated (“programmed”) somehow to undergo aldol and Claisen reactions to form specific cyclic products. The domain architecture of the non-reducing IPKSs is conserved as illustrated by PksA, the protein responsible for norsolorinic acid anthrone (noranthrone) synthesis, the earliest precursor to the environmental toxin aflatoxin B1. In this case the “starter unit acyltransferase” (SAT) domain receives a hexanoyl unit from a dedicated short-chain fatty acid synthase. Seven canonical acetyl extensions take place by decarboxylative thio-Claisen condensation with seven successive units from malonylCoA introduced by the MAT domain. Evidence will be presented that the fully extended (C20) poly-b-keto chain is bound in the “product template” (PT) domain where two regiospecific intramolecular aldol (as well as dehydration and aromatization) reactions occur to yield the trihydroxynaphthalene ACP–thioester, which then undergoes final Claisen cyclization to noranthrone. X-Ray crystal structures of both the PksA PT, and TE domains obtained in collaboration the Tsai group at U. C. Irvine will be discussed. Mutational experiments have been conducted to test proposed functions of these proteins.