Non-melanoma skin cancers are among the most commonly diagnosed skin cancers in the world. Ultraviolet radiation is a primary carcinogen resulting in UV induced mutations, loss of activity in tumour suppressor genes and the over expression of oncogenes in keratinocytes resulting in the development of skin malignancies. With the continued rising rate of non-melanoma skin cancer, topical therapies have become an established treatment method for effective lesion clearance. Current topical therapies include 5-fluorouracil, imiquimod, diclofenac, ingenol mebutate and photodynamic therapy. With high lesion recurrence rates still presenting as an issue following topical treatment, lack of drug selectivity for cancer cells, severe side effects from topical agent use and patient non-compliance due to prolonged treatment periods, new novel topical therapies need to be explored and developed. New therapies must target and clear both subclinical and clinically presenting skin cancers by interrupting the molecular mechanisms that induce and sustain the proliferation of neoplastic cells. Piperlongumine and EBC-46 are two naturally occurring small molecules which have demonstrated effective induction of cancer cell death. Piperlongumine, an amide isolated from the pepper, Piper longum, has demonstrated cancer cell death selectivity yet has no impact on healthy rapidly dividing primary cells. EBC-46 is a diterpene ester isolated from the seed of the fruit, Fontainea picrosperma. EBC-46 induces rapid inflammation and necrosis resulting in tumour ablation following intra-lesional injection. The development of Piperlongumine and EBC-46, as new topical agents offers a unique opportunity to further explore and exploit these selective properties for a more efficient and targeted approach to topical non -melanoma skin cancer treatment.