Urothelial carcinomas (UCs) are a group of malignancies with high prevalence in Western countries. Among patients diagnosed with UC, approximately 5–10% present with upper tract urothelial carcinomas (UTUCs), which can be located in the renal pelvis, calyces, or ureters. However, due to their low prevalence much remains unknown about the genetic and immune contexture of these tumors. UTUC represents an aggressive malignancy that can be of sporadic or hereditary origin, as part of Lynch syndrome. A deeper understanding of UTUC’s molecular landscape has been accomplished with recent next-generation sequencing studies supporting a luminal papillary, T cell-depleted contexture, and activated FGFR3 signaling. Therapeutic management of these patients remains a challenge in daily clinical practice but is also rapidly evolving. In localized disease, radical nephroureterectomy and adjuvant chemotherapy remain the standard of care, while in the locally advanced and metastatic settings the entry of novel immune checkpoint inhibitors into the therapeutic armamentarium beyond platinum-based therapies has altered the prognosis of this devastating disease. Novel agents including the antibody-drug conjugates (ADCs) enfortumab vedotin and sacituzumab govitecan as well as targeting the FGFR axis with erdafitinib and other kinase inhibitors have already transformed treatment selection algorithms in these patients. Development of robust predictive and prognostic biomarkers is urgently needed to guide a more individualized treatment approach for each patient in order to maximize clinical benefit and further improved outcomes.