<p>Conventional cancer therapies, particularly oral and intravenous chemotherapy, are frequently associated with systemic toxicity, non-specific drug distribution, fluctuating plasma concentrations, and limited patient compliance. These drawbacks have led to the development of alternative drug delivery strategies which aimed at improving therapeutic potency with minimized adverse effects. Transdermal drug delivery systems (TDDS) have emerged as a promising non-invasive technology that possesses the ability to offer sustained and controlled drug release, avoiding first-pass metabolism, and reducing systemic exposure. In the context of cancer treatment, TDDS allows for localized drug delivery and optimized pharmacokinetic control, thereby enhancing therapeutic index. Recent formulation advancements in the area of polymeric patches, microneedles, nanoliposomes, lipid and polymeric nanoparticles, nanoemulsions and physical enhancement methods such as iontophoresis and electroporation have greatly improved skin permeability and drug stability. The application of nanotechnology has also enabled the development of targeted, stimulus-responsive, and immune-modulating delivery systems. Despite the challenges posed by skin barrier function, penetration of high molecular weight drugs, interpatient variability, and translational issues, ongoing preclinical and clinical studies demonstrate the growing promise of TDDS primarily in localized and superficial malignancies, such as melanoma and non-melanoma skin cancers, with systemic applications remaining largely at the preclinical stage. This review critically evaluates the existing formulation approaches, molecular mechanisms, clinical efficacy and future prospects of TDDS in cancer treatment.</p> Graphical Abstract <p></p>