Cyclodipeptides and their derivatives, the diketopiperazines (DKPs), constitute a large class of natural products that exhibit various biological properties. Until recently, there are a few characterized DKP biosynthetic pathways. In all these cases, the formation of the cyclodipeptides that harbor the DKP scaffold is catalyzed either by nonribosomal peptide synthetases or by cyclodipeptide synthases. This review focuses on the DKP biosynthetic pathways and their associated molecular mechanisms.