The phenyl group is the most prevalent ring system and plays an essential role as a pharmacophore or scaffold in marketed drugs. However, the indiscriminate employment of phenyl is also a major cause of poor physicochemical properties of active molecules. Nonclassical phenyl bioisosteres (NPBs) have emerged as effective replacements for phenyl in structural optimization due to their unique steric structures and physicochemical properties. Herein, the effects of widely reported NPBs on physicochemical properties and biological activities, including bicyclo[1.1.1]pentane (BCP), bicyclo[2.1.1]hexanes (BCH), bicyclo[2.2.2]octane (BCO), cubane (CUB) and closo-carboborane, are reviewed. Issues that require consideration while using NPBs and practical solutions to problems frequently encountered in structural optimization using NPBs are also discussed.