Recent insights into the molecular and immunologic complexity of urothelial carcinoma (UC) have redefined its therapeutic paradigm, revealing both opportunities and limitations of precision oncology as targeted therapies, immune checkpoint therapies (ICTs), and antibody–drug conjugates (ADCs) reshape clinical outcomes while resistance, tumor heterogeneity, and the lack of validated biomarkers continue to constrain durable benefit; this chapter examines how integrating biomarker discovery with therapeutic innovation is transforming UC management through clinically actionable targets such as Nectin-4, Trop-2, and the Fibroblast Growth Factor Receptors (FGFR) and HER2 receptor families that underpin ADC and monoclonal antibody development, genomic and metabolic vulnerabilities including MTAP loss that intersect with immune modulation, and immuno-oncology markers such as PD-L1 expression, tumor mutational burden (TMB), microsatellite instability (MSI), and DNA damage response (DDR) alterations that guide response to ICT, by synthesizing translational and clinical evidence; this chapter delineates how these biomarkers collectively support patient selection, combination strategies, and future biomarker-guided therapeutic refinement in urothelial carcinoma.