Nitrogen-containing heterocycles represent a major source of pharmacological probes and drug candidates. To extend their molecular diversity and their potential biological activities, it is of importance to design and synthesize new N-heterocyclic scaffolds. Therefore, aza-diketopiperazines (aza-DKPs), the aza analogues of well-known 2,5-diketopiperazines (DKPs), emerged as a promising new scaffold. Although the first synthesis of an aza-DKP dates from 1951, significant developments have been made during the last decade. This feature article summarizes the different synthetic strategies to access and functionalise aza-DKPs. Their biological properties and potential applications in medicinal chemistry and drug discovery are discussed as well.