Therapies for genitourinary malignancies have evolved considerably in the past five years. Combination treatment targeting biologically relevant immune and angiogenic pathways is improving patient survival in metastatic renal cell carcinoma (RCC), whereas immune checkpoint blockade (ICB), novel targeted therapy, and antibody drug conjugates have changed the landscape of urothelial cancer (UC) treatment. A daily challenge for clinicians is identifying patients who derive a preferential benefit from the available therapeutic options. The completion of large-scale genomics projects has yielded comprehensive descriptions of the molecular heterogeneity present in RCC and UC, although clinical applications of these data continue to evolve. Major molecular subtypes of RCC align well with histology subtype, and although some molecular characteristics appear to carry prognostic information, biomarkers predicting benefit from tyrosine kinase inhibitor (TKI) or immunotherapy are generally lacking. Unexpectedly, similar work has demonstrated that UC can be grouped into “molecular subtypes” that share properties with those found in breast cancer and other solid tumors. Furthermore, this molecular subtype classification is prognostic and potentially predictive of differential benefit from conventional and targeted therapies. This article provides an update on the current state of molecular biomarker development and potential clinical utility in RCC and UC.