ABSTRACT Upper tract urothelial carcinoma (UTUC) is a rare and aggressive disease that is associated with high rates of recurrence and death. Radical nephroureterectomy (RNU) with excision of the bladder cuff is considered the standard of care for high-risk UTUC, whereas kidney-sparing techniques can be indicated for select patients with low-risk disease. There is a significant lack of clinical and pathological prognostic factors for stratifying patients with regard to making treatment decisions. Incorporation of tissue-based molecular markers into prognostic tools could help accurately stratify patients for clinical decision-making in this heterogeneous disease. Although the number of studies on tissue-based markers in UTUC has risen dramatically in the past several years—many of which are based on single centers and small cohorts, with a low level of evidence—many discrepancies remain between their results. Nevertheless, certain biomarkers are promising tools, necessitating prospective multi-institution studies to validate their function.