Actinic keratosis, commonly indicative of photodamage, requires treatment secondary to the risk of progression to squamous cell carcinoma. A number of effective treatments for actinic keratosis are available, including topical and lesion-directed therapies. While lesion-directed therapies such as cryotherapy are appropriate for isolated lesions, topical 5-fluorouracil is an effective modality for the treatment of multiple facial actinic keratoses. 5-Fluorouracil, available in a number of formulations, offers patients the benefit of treating subclinical lesions and may help to improve the overall appearance of the skin. In many cases, combination therapy is a better treatment option than monotherapy. The cases presented here demonstrate the use of topical 5-fluorouracil cream 0.5% as monotherapy and in conjunction with glycolic acid peels to treat facial actinic keratoses in two patients with extensive histories of prior actinic keratosis and skin cancer.