Topical imiquimod 5% cream is approved for the treatment of actinic keratosis (AK), superficial basal cell carcinoma, and external genital warts. The drug’s mechanism of action is via stimulation of innate and acquired immune responses, which ultimately leads to inflammatory cell infiltration within the field of drug application followed by apoptosis of diseased tissue. This article reviews available data on the use of topical imiquimod for AK. Topical imiquimod is an effective and safe treatment option for AK that produces complete eradication or marked reduction in the number of lesions in most patients. Subclinical lesions also emerge during treatment of the affected skin region (“field treatment”). In addition, there is evidence that topical imiquimod at least partially reverses some of the cellular, molecular, and genetic photocarcinogenic changes that develop in skin damaged by UV light. Recent evidence suggests that many patients who effectively are cleared of AK lesions after topical imiquimod use remain free of lesions for several months to 2 years or develop a minimal number of new AK lesions.