Covering: 1996-2022 Investigations over the last 2 decades have begun to reveal how fungal iterative highly-reducing polyketide synthases are programmed. Both in vitro and in vivo experiments have revealed the interplay of intrinsic and extrinsic selectivity of the component catalytic domains of these systems. Structural biology has begun to provide high resolution structures of hr-PKS that can be used as the basis for their engineering and reprogramming, but progress to-date remains rudimentary. However, significant opportunities exist for translating the current level of understanding into the ability to rationally re-engineer these highly efficient systems for the production of important biologically active compounds through biotechnology.