Four-membered rings can generally withstand practical applications despite their stereoelectronic distortion. Recently, they have attracted particular attention in the field of drug discovery because of their conformational rigidity. In particular, oxetane and azetidine are known for their polarity, which arises from the heteroatoms, i.e., oxygen and nitrogen, respectively. Bioactive molecules designed to incorporate these motifs are expected to show high selectivity for target proteins, as well as other beneficial properties such as hydrophilicity, solubility, and metabolic stability. Notably, following the milestone study by Carreira et al., who revealed that 3,3-disubstituted oxetanes are bioisosteres of carbonyl or gem-dimethyl groups, the construction and metabolism of the oxetane motif have been extensively explored (Figure ). Stepan et al. reported that gem-dimethyloxetane shows slightly higher metabolic stability than do 3,3-disubstituted oxetanes in a -secretase inhibitor designed by the researchers. Fish et al. reported an EC50 improvement by azetidine incorporation into the 5-HT2C agonist. The oxetane or azetidine motif can be also found in the structure of biologically active natural products and commercial drugs (e.g., paclitaxel and azelnidipine). Recently, synthetic methods for four-membered heterocycles have been reinvestigated to meet the high demand for these compounds in drug discovery, and this places high priority on the three dimensionality of small molecules (Figure ). A typical synthetic method applicable to both oxetane and azetidine is intramolecular displacement. This reaction is particularly suitable for the synthesis of 3-substituted or 3,3-disubstituted compounds, and it has been widely exploited in drug discovery. Other reactions have also been adopted to synthesize four-membered heterocycles, with varying degrees of success. Halocyclization of alkenes has not been extensively explored for synthesizing polysubstituted four-membered heterocycles. Stepan et al. utilized halocyclization to synthesize their target compound, and the product was obtained in a low yield. While Paternò-Büchi-type reactions are known to be suitable for polysubstituted four-membered heterocycles, structural requirements are necessary to facilitate photoactivation. There are other synthetic methods to construct oxetane and/or azetidine such as ring-expansion using ylide, 10 -lactam reduction, C-H bond amination, and Ti VI -mediated spirocyclic azetidine synthesis. Overall, the synthesis of less hindered oxetanes or azetidines is facile owing to classical intramolecular displacement reactions. However, new synthetic methods for sterically hindered and polysubstituted products are required.