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Background Topical immunomodulatory therapy with imiquimod has been recently used for the treatment of actinic keratoses, intraepithelial carcinoma, and small basal cell carcinoma (BCC) besides the licensed indication of extragenital warts (condyloma). Methods We treated several patients with particular epidermal neoplasias such as squamous cell cancer (SCC) and basal cell cancer of sclerodermiform type three times per week for 4 to 12 weeks. Results We report several novel aspects of the treatment of epidermal cancers with self-applied, nonpainful, immunomodulatory therapy. First, we treated—for the first time—two immunosuppressed renal transplant patients for invasive SCC with imiquimod. Interestingly, systemic immunosuppression did not adversely affect the response to therapy. Second, one patient with the high-risk and aggressive growth pattern of basal cell cancer (sclerodermiform histology) was cured from his disease at a particular location in the face, suggesting sufficient penetration despite scarring. No recurrence was detected in another patient who suffered from 29 BCCs until almost 2-years follow-up. Third, the treatment of actinic keratoses in the face is substantially shorter (in the order of 4 to 6 weeks) as opposed to other skin cancers. Immunomodulatory treatment with imiquimod led to the demarcation of in situ actinic keratosis lesions that could not be identified using the dermatologist's experience, probably because of the existence of exclusive alterations on the molecular level. Conclusion Several novel aspects of immunomodulatory treatment with imiquimod and new indications such as selected cases of sclerodermiform BCC and SCC have been described. The texture of the skin at various different body locations may explain the varying sensitivities to imiquimod when facial skin is compared with skin on the extremities.