With an incidence of 0.1-0.9/100,000 men/year, penile cancer is a rare cancer of the urogenital tract in Western Europe. At the time of initial diagnosis up to 45% of the patients already demonstrate metastatic disease and need some type of systemic treatment. Objective remission rates and 3-year survival rates of 30 and < 10%, respectively, are depressingly low. Identification of molecular targets for the introduction of molecular triggered therapies such as monoclonal antibodies and tyrosine kinase inhibitors might improve the poor prognosis and could replace non-targeted systemic chemotherapies with a less toxic targeted therapy.However, a MEDLINE search does not identify any current clinical trial with regard to targeted therapeutic approaches in penile cancer. Based on a systematic review of the molecular events involved in the metastatic process of penile cancer, therapeutic approaches with bevacizumab or COX-2 inhibitors appear to have the greatest potential to improve the prognosis. In order to perform a prospective clinical phase 2/3 trial in such a low frequency cancer, international cooperative structures have to be established.