Magnetic Resonance Imaging (MRI) plays a vital role in the accurate diagnosis of numerous human diseases and disorders, with Gd(III)-based contrast agents (GBCAs) being used in ≈30%-40% of procedures, resulting in ≈30 million doses administered annually worldwide. The careful design of a rigid macrocyclic chelator featuring a highly hydrophilic periphery leads to the development of gadopiclenol, the first bis-hydrated Gd(III)-based MRI contrast agent, recently approved for clinical use by both the FDA and EMA. The stereochemistry of the coordinating arms is found to play a crucial role in the remarkable thermodynamic stability and inertness of the Gd(III)-complex with the RRR/SSS-stereoisomer of this heptadentate chelating agent, ensuring its safety in vivo. The exceptional stability of the most effective gadopiclenol enantiomeric pair (RRR/SSS), coupled with a relaxivity 2 to 3 times higher than that of currently used GBCAs, has enabled the use of reduced doses while ensuring non-inferior image contrast.