Actinic keratosis (AK) is considered as a superficial squamous cell carcinoma (SCC). A central role in the pathogenesis is played by chronic sun exposure. UVB causes direct damage to DNA, producing pyrimidine dimers, and suppressing the protective role of p53. The stepwise progression of AK, with an increased expression of anti-apoptotic Bcl-2, favors the progression to SCC. Moreover, the dermal response characterized by inflammation and mediated by prostaglandins is a critical component of tumorigenesis that promotes tumor growth, tissue invasion, angiogenesis and metastasis. Other risk factors are represented by age, gender, photo type and drugs. Areas Covered: In this review, the authors have documented the different therapies planned for AKs involved in the pathogenesis phases. It is also possible to propose to the patient a rotational approach to control the subclinical lesions present in the cancerization field. Therapy should be individualized, based on features of AK lesions, clinical evidence of severity cancerization field, patient’s medical status and needs and previous AKs’ treatment strategies. Expert Opinion: The usefulness of long-term treatment with piroxicam and sun filters or diclofenac targeting the inflammation phases of skin tumorigenesis favors AKs’ healing and determine greater control of cancerization field. Nonsteroidal anti-inflammatory drugs can be safely used in patients who use photosensitizing drugs and, therefore, are more at risk of developing skin tumors. Instead, immunomodulatory therapies, which require shorter treatment, are characterized by more common local side effects. Patient education in dermatology results in improved adherence and outcomes.