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Tertiary Alcohol: Reaping the Benefits but Minimizing the Drawbacks of Hydroxy Groups in Drug Discovery Among the smaller substituents in the medicinal chemist’s toolbox, the hydroxy (OH) group can bestow one of the largest impacts in the drug-like properties of a molecule. A previous study showed that an H-to-OH structural modification effectively decreases lipophilicity, increases solubility, and decreases hERG inhibition. Despite these benefits, an OH group is not always recommended in drug molecules because it presents a metabolic “soft spot” for oxidation and glucuronidation in primary and secondary alcohols. Furthermore, the OH group presents challenges in permeability. In contrast, tertiary alcohols (3° ROH) often display an improved metabolic profile because oxidation at the 3° ROH is not possible, and the geminal alkyl groups could sterically shield the OH group from glucuronidation and permeability challenges. Through a series of matched molecular pairs, this Perspective highlights the 3° ROH as a motif that can reap the benefits but minimize the drawbacks of hydroxy groups in drug discovery. https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c03078?ref=PDF