AbstractAlthough studies in drug discovery have gained momentum in recent years, the conversion of drugs in use today into less toxic derivatives with pharmacologically superior properties is still of great importance in drug research. Bioisosterism facilitates the conversion of drugs into derivatives that present more positive pharmacological and toxicological profiles by changing existing groups in the drug structure within the framework of certain criteria that have been expanded today. The 1,2,4‐oxadiazole ring is used as a bioisostere for ester and amide groups due to its resistance to hydrolysis. However, this ring is not limited to esters and amides, but can also be used as a bioisostere for other functional groups. In this review, cases in which the 1,2,4‐oxadiazole ring is used as a bioisostere for various functional groups are discussed. Herein we shed light on 1,2,4‐oxadiazole bioisosterism in the development of new drug candidates and in enhancing the pharmacological profiles of currently available drugs.