The renin–angiotensin system (RAS) is central to regulation of blood pressure and electrolyte homeostasis.  Angiotensin‐converting enzyme (ACE), a key protease in the RAS, has a range of substrates, including N‐acetyl‐Ser‐Asp‐Lys‐Pro (Ac‐SDKP). The peptide Ac‐SDKP is cleared almost exclusively by ACE, and specifically by the N‐domain active site of this enzyme.  N‐Acetyl‐Ser‐Asp‐Lys‐Pro is a negative regulator of haematopoietic stem cell differentiation and is a potent antifibrotic agent. In this review, the physiological actions of Ac‐SDKP are presented, together with the potential clinical usefulness of raising Ac‐SDKP levels. This emphasizes the possible opportunity of N‐domain‐selective ACE inhibitors or ACE‐resistant Ac‐SDKP analogues for the treatment of fibrosis.