Precise control of molecular properties and conformation is essential in drug discovery. Effective interactions with targeted biological sites require complementary electron density surfaces, modulated through combinations of polar, aromatic and hydrophobic sites. Small polar groups such as oxetanes, 2 sulfoximines 3 and phosphine oxides have emerged as valuable bioisosteres that mimic the spatial electronic properties of more common functional groups and potentially enhance binding through tailoring polarity and H-bonding properties. These groups are also beneficial in providing increased 3-dimensionality and in influencing metabolic stability, solubility, absorption, distribution and pKa. Thus, these small polar motifs have provided genuine new design options to medicinal chemists. Oxetanes are a notable example of such a motif, with nine oxetane containing compounds currently in clinical trials (Figure ). Carreira's seminal studies established oxetanes as valuable replacements for carbonyl and gem-dimethyl functionalities, expanding their medicinal chemistry potential by advancing the chemistry of oxetanone and oxetane-Michael acceptors. We have demonstrated the Lewis and Brønsted acid-catalyzed formation of oxetane carbocations from oxetanols, facilitating trapping with arenes, thiols, and alcohols to generate 3,3-disubstituted derivatives (Figure ). Very recently, Zhang and coworkers also developed a Lewis acid activation of oxetanyl trichloroacetimidates for the generation of oxetane carbocations. These advancements, along with the development of alternative electrophiles and other cross-coupling and radical processes, 12 accentuate the significance of oxetanes in drug discovery. Similarly, azetidines are undergoing extensive investigation and though less represented than their five-and sixmembered counterparts are rapidly gaining prominence in approved drugs (Figure ). Pioneering work by Baran stimulated the adoption of azabicyclo[1.1.0]butane (ABB) strain-release reagents, enabling late-stage 'azetidinylation' of secondary amines (Figure ). Aggarwal leveraged 3lithiated ABBs as nucleophiles in the modular synthesis of azetidine scaffolds. Radical processes 18 and additions to alkylidene-azetidines have been developed to generate valuable 3,3-substiuted azetidine derivatives.