Treating advanced penile cancer: where do we stand in 2019? Purpose of review Penile squamous cell carcinoma (PSCC) remains a challenging malignancy to treat and there is an urgent need of significant improvements at all levels of medical care. In the current review, we summarized the significant obstacles encountered during management of PSCC and discussed the clinical relevance of novel findings and their potential to address these obstacles. Recent findings The recent genetic and immunological advances suggest that patients with PSCC can benefit from available targeted therapy and immunotherapy options. Moreover, evidence has accumulated over time suggesting that majority of the patients diagnosed with PSCC suffer from psychosocial problems and impaired rehabilitation. Summary Effective prevention strategies against PSCC are urgently needed especially in developing countries given the limited therapeutic options. About a quarter of patients with metastatic PSCC appear to benefit from available targeted therapies and about half of the patients can be a suitable candidate for immune checkpoint blockade as half of the PSCC cases exhibit PD-L1 expression. Moreover, increased public awareness, healthcare provider education and social support programs may help patients suffering from PSCC coping with the psychosocial burdens of the disease. Correspondence to Philippe E. Spiess, MD, MS, FRCS(C), FACS, Senior Member, Department of GU Oncology, Senior Member, Department of Tumor Biology, Department of Genitourinary Oncology, Assistant Chief of Surgical Services, Moffitt Cancer Center, Professor, Department of Urology, University of South Florida, FL 33612, USA. Tel: +1 813 745 2484; fax: +1 813 745 8494; e-mail: philippe.spiess@moffitt.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.