Several polyketopiperazines represent the simplest heterocyclic compounds found in nature, acting as a vital base-structure for many bioactive compounds. They are widely distributed in microorganisms, food, and beverages with diverse bioactivities, such as antiviral, anticancer, antioxidant, and neuroprotective properties. Focusing on triketopiperazines and tetraketopiperazines; triketopiperazines possess important biological properties and used for production of the valuable molecular scaffolds in synthetic biology, whereas tetraketopiperazines are economically beneficial for chemical engineering. Noteworthy, they have extra-rigid conformations and are more resistant to degradation by enzymes. Therefore, they represent an interesting subclass of heterocycles with high potential to be used in the production of new effective therapeutic motif and sustainable energy storage structures.