This review examines the commonly available topical acne agents and factors that determine their percutaneous absorption. Reported and theoretical adverse effects from systemic exposure are detailed. The topical retinoid class, which includes tretinoin, adapalene and tazarotene, and the topical antibacterials, clindamycin and erythromycin, are regulated by prescription in most countries. Used appropriately, the above-mentioned drugs deliver, at most, miniscule amounts of active ingredient into the circulation. Clear-cut links to systemic toxicity in humans are practically nonexistent, except in the case of topical clindamycin, which has been associated with diarrhea rarely, and there have been 2 cases of pseudomembranous colitis reported. Birth defects have occurred in two patients treated with tretinoin and one patient treated with adapalene, but causation was not proven. Another prescription drug, 20% azelaic acid, is associated with relatively high systemic exposure, which is presumed innocuous because it is a normal dietary constituent whose endogenous levels are not altered by topical use. Benzoyl peroxide, salicylic acid, sulfur, and sodium sulfacetamide are available in concentrations of 2% or more in over-the-counter acne treatments and some prescription products. All of these agents are known to exhibit some degree of percutaneous absorption. They remain largely unregulated because, other than skin irritation, only local allergic contact dermatitis from benzoyl peroxide in about 2.5% of patients and rare local and systemic hypersensitivity reactions from sodium sulfacetamide have been reported. Salicylism has occurred using methyl salicylate ointments and high concentrations of salicylic acid on widespread areas of hyperkeratotic skin, but there are no known cases resulting from salicylic acid acne products. Caution is advised in special circumstances, such as during childhood, pregnancy, lactation and concomitant therapy with other drugs, because relevant studies are lacking. Animal data support avoidance of many topical agents, particularly known teratogens such as retinoids and salicylic acid, in pregnant women. Salicylate avoidance is advised during lactation, because aspirin use carries the risk of bleeding disorders in nursing infants.