Hydrogen peroxide (H2O2) is an endogenous reactive oxygen species that contributes to oxidative stress directly as a molecular oxidant and indirectly through free radical generation. Topically applied 1% to 45% H2O2 can be used for a range of clinical purposes, which will be reviewed here in addition to its safety. In concentrations from 1% to 6%, H2O2 has antimicrobial properties and can act as a debriding agent through its effervescence, making low-concentration H2O2 useful for wound care. H2O2 has also been shown to promote venous insufficiency ulcer healing, but studies in other wound types are needed. In 1% formulations, H2O2 is used outside the United States to treat acne and has shown efficacy similar to or greater than benzoyl peroxide, with reduced side effects. In a concentration of 40%, H2O2 is US Food and Drug Administration–approved to treat seborrheic keratoses and may cause fewer pigmentary changes than cryotherapy, although elimination often requires 2 to 4 treatments. However, H2O2 should be used with caution, as exposure can cause adverse effects through its oxidant capabilities. Low H2O2 concentrations cause only transient symptoms (blanching and blistering), but exposure to 9% to 45% H2O2 can cause more severe skin damage, including epidermal necrosis leading to erythema and bullae. Overall, H2O2 has numerous therapeutic uses, and novel indications, such as treating actinic keratoses and skin cancers, continue to be explored.