Actinic keratosis (AK) constitutes the initial epidermal lesion in a disease continuum that may progress to invasive squamous cell carcinoma (SCC). A number of treatment options are available to clear lesions, and thus reduce the risk for progression. Field-directed approaches are primarily used to clear multiple AKs and subclinical lesions. Current field-directed approaches still have a number of unmet needs, and a number of investigational agents are being evaluated. Topical therapy can be improved by shortening treatment periods; enhancing tolerability, compliance, and patient satisfaction; reducing recurrence rates; and lowering cost. This 2-part review will explain the role of field-directed therapy in the treatment of AK. Part 1 focuses mainly on investigational agents that are being studied for topical patient-administered, field-directed therapy.