The use of epidermal growth factor receptor (EGFR) inhibitors in several epithelial tumors has increased considerably in recent years. Currently, they are approved in non-small cell lung cancer (NSCLC), pancreatic cancer, colorectal cancer and head and neck cancer. Skin toxicity is a class-specific side effect that is typically manifested as a papulopustular rash in the majority (45-100%) of patients receiving EGFR inhibitors. The skin toxicity is related to the inhibition of EGFR in the skin, which is crucial for the normal development and physiology of the epidermis. Although rarely life-threatening, skin toxicity may cause significant physical and psycho-social discomfort. Nevertheless, the presence and severity of skin rash is associated with improved clinical efficacy in patients receiving EGFR inhibitors. The goal of managing EGFR inhibitor-associated skin toxicity is to minimize the detrimental effects of the rash on patients' quality of life and treatment course without antagonizing the clinical efficacy of EGFR inhibitors. There is currently no evidence-based treatment guideline to prevent or treat the EGFR inhibitor-associated skin toxicities. Expert panels recommend a proactive, multidisciplinary approach that includes patient education and the use of a grade-based treatment algorithm. Elucidation of the mechanisms of EGFR inhibitor-associated skin toxicity and development of mechanism-based novel therapies are urgently needed. Preclinical data suggest topical application of a potent phosphatase inhibitor menadione (Vitamin K3) can rescue the inhibition of EGFR and downstream signaling molecules in the skin of mice receiving systemic EGFR inhibitor erlotinib or cetuximab. A randomized, double-blinded, placebo-controlled study has been initiated to evaluate the clinical efficacy of menadione topical cream, in the treatment or prevention of EGFR inhibitor-induced skin toxicity.