Squamous cell carcinoma of the penis is a heterogeneous disease with 14 different histological subtypes which have differing molecular oncological features, varying relations with high-risk papillomaviruses and different metastatic potential and prognosis. Despite recent advances in the understanding of the molecular changes associated with penile cancer, individualized treatment is not available. Targeted and immunotherapy approaches to penile cancer do not yet have a defined role in penile cancer although trials are being conducted. Chemotherapy is the main option for systemic treatment in penile cancer and several drugs are effective against it. Two triple-drug regimens based on cisplatin and taxanes with proven efficacy are available. The most effective use of chemotherapy in penile cancer is together with radical lymph node surgery in patients with limited inguinal and pelvic lymph node disease. In that setting, chemotherapy can be curative. Controversy still exists as to the timing of chemotherapy, whether it should be neoadjuvant or adjuvant. Response to chemotherapy cannot be predicted and nonresponders do not have a good prognosis.