The conformational restriction (rigidification) of a flexible ligand has often been a commonly used strategy in drug design, as it can minimize the entropic loss associated with the ligand adopting a preferred conformation for binding, which leads to enhanced potency for a given physiological target, improved selectivity for isoforms and reduced the possibility of drug metabolism. Therefore, the application of conformational restriction strategy is a core aspect of drug discovery and development that is widely practiced by medicinal chemists either deliberately or subliminally. The present review will highlight current representative examples and a brief overview on the rational design of conformationally restricted agents as well as discuss its advantages over the flexible counterparts.