Topical ophthalmic corticosteroids are of clinical benefit in the management of pain and inflammation after ocular surgery; however, their use can be associated with class-associated adverse events (AEs) and limited bioavailability. Selection of an appropriate topical corticosteroid depends on drug-specific variables such as AE profile, efficacy, potency, dosing, patient-specific administration needs, and formulation properties aimed at minimizing precorneal drug loss, increasing ocular surface drug residence time, and maximizing drug delivery to the anterior tissues. Recently, strategies for improving ocular penetration of ophthalmic formulations have included use of mucoadhesive formulations (ie, polycarbophil-containing gels) and drug particle size reduction, enabling faster drug dissolution and therefore increased bioavailability and penetration. Loteprednol etabonate (LE) is a carbon-20 ester corticosteroid developed through retrometabolic drug design with potent anti-inflammatory effects and a reduced propensity for eliciting corticosteroid class AEs. This drug has been formulated for topical ophthalmic use after surgery as 0.5% and 1% suspensions, a 0.5% ointment, and a 0.5% gel. Preclinical and clinical data for a new 0.38% LE gel will be reviewed demonstrating that reducing the drug particle size to the nanometer range in diameter provides effective ocular tissue penetration and resolution of pain and inflammation despite a reduced drug concentration (0.38%) and dosing frequency.