Direct functionalization of the extensive existing library of lead compounds with unconventional ring motifs opens up exciting new chemical space for medicinal chemists (Figure ). However, introducing such rings is often more challenging than synthesizing the lead compounds themselves. In this context, several elegant approaches have emerged for directly attaching unique ring motifs, such as bicyclopentanes, cubanes, cyclobutanes, oxetanes, and azetidines, to biorelevant structures, allowing practitioners to refocus on the challenge of synthesizing molecular scaffolds rather than the difficulties posed by these unique ring systems. As a class of privileged ring motifs, azetidines, small and strained nitrogen-containing heterocycles, offer various desirable attributes for drug development, such as innate rigidity, enhanced solubility, and improved metabolic stability. Figure showcases some representative bioactive molecules featuring the azetidine ring.