Here, we focus on the only two known CDPS enzymes which synthesise bioactive histidine-containing cyclic dipeptides (Scheme 1). Cyclo(His-Phe) (cHF) encompasses the backbone structure of the anti-tumour compound plinabulin, while cyclo(His-Pro) (cHP) is endogenous to the human body and proposed as a neuroprotective peptide against Parkinson's disease and amyotrophic lateral sclerosis, as well as a molecule involved in the gut-brain-axis crosstalk, with effects on glucose metabolism. Thus, it would be advantageous to expand the chemical space of histidine-containing cyclic dipeptide analogues we could produce by using CDPS enzymes.