Chronic, long-term sun exposure results in genetic changes in epidermal keratinocytes and the development of various skin lesions ranging from actinic keratosis (AK) to skin cancer. AK lesions may first appear as rough, scaly spots on sun-exposed skin, and, although most individual AK lesions do not become invasive cancers, the majority of invasive squamous cell carcinomas originate from AK. Genetic analysis demonstrates that ultraviolet radiation–induced mutations and changes in gene expression are present in squamous cell carcinoma, AK, and clinically normal-appearing perilesional sun-exposed skin, which supports the progressive nature of keratinocyte transformation. The presence of certain clinical features, such as large size, ulceration, or bleeding, suggests an increased risk of disease progression. The risk is also increased by evidence of extensive solar damage, advanced age, and immunosuppression. Early diagnosis and consideration for treatment are indicated to clear actinically damaged sites and diminish the risk of invasive squamous cell carcinoma.