Promising approaches had been adapted for the treatment of skin cancer to eliminate the need for surgery and get rid of scars that disfigure the patient’s skin, as well as overcome the serious side effects of oral regimens. Topical applications with new modified formulation technologies enhanced skin permeation and localization in the dermal region in a solubilized form that enhanced drug diffusion in the tumor tissue, eradicating cancer cells at the early stages of diagnosis. In addition, advancements in photodynamic therapy refined the approach of combining light with a photosensitizer (drug) to transfer energy to nearby oxygen in the tissue, generating reactive oxygen species that effectively destroy tumor cells via apoptosis, necrosis, and autophagy-associated cell death. Recent application of magnetic field have reported reduction in tumor size in vivo. Preclinical testing in vitro evaluation such as using confocal microscopy and cell line-derived xenografts gained good prominence as well as in vivo testing using isotopes as Phosphorus-32 (P32), MRI follow up using a contrast agent or patient-derived xenograft (PDX) models to detect and calculate the tumor size and its response to the treatment were successfully applied. Additionally, the integration of artificial intelligence (AI) into drug discovery have accelerated the identification of potential therapeutic compounds. AI algorithms analyze vast datasets to predict the efficacy and safety profiles of new drugs, streamlining the preclinical phase and enhancing the success rate of subsequent clinical trials to improve patient outcomes.