The 2 primary classes of drugs used to treat atopic dermatitis (AD) are topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). For maximum efficacy, topical agents must efficiently penetrate the skin but, for optimal safety, should not be absorbed into the bloodstream. TCSs, a mainstay in AD treatment for more than 50 years, can potentially be absorbed into the systemic circulation, particularly when used on young children, for prolonged periods, or on areas of thin and sensitive skin, such as the eyelids, face, and flexures. There is a risk of cutaneous and systemic adverse events, including suppression of the hypothalamic-pituitary-adrenal axis and related sequelae, especially when potent or superpotent TCSs are used for extended periods. Ideally, TCSs should be used for short periods (2-4 weeks), but clinical reality often necessitates longer use. TCIs also effectively and safely treat AD, with the most commonly observed local adverse events being skin irritation and burning. These agents have demonstrated good penetration of the skin with minimal systemic absorption, as evidenced by low blood concentrations, and can be used safely on thin and sensitive skin. The use of mid-potency TCSs to treat acute flares involving skin of normal thickness, followed by the introduction of TCIs for maintenance therapy, constitutes an appropriate application of both drug classes. Pharmacists with a clear understanding of how both types of agents affect the systemic circulation have the opportunity to inform patients and caregivers about benefits and limitations of different therapeutic agents, address patient concerns about adverse events, and help patients understand how to use medical therapies appropriately.