Although relatively rare in Western countries, penile cancer is associated with high morbidity and mortality. To achieve the most favorable outcomes in men with this malignancy, early medical or surgical treatment is required. Few data are available from prospective, randomized trials, and heterogeneous approaches to care have emerged. In this article, Dr. Spiess presents highlights from the inaugural NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for penile cancer, focusing primarily on treatment strategies for primary penile lesions and regional lymph nodes. NCCN recommendations regarding surveillance and the management of tumor recurrence and metastatic disease are briefly explored.