Metastatic renal cell carcinoma (mRCC) comprises a highly heterogeneous group of diseases with varied clinical outcomes. As a result, models to estimate prognosis were developed in an attempt to aid patient counseling, treatment selection, and clinical trial design. Contemporary prognostic models have been mostly generated based on clinical factors because of their ease of use. Recent advances in molecular techniques have allowed unprecedented molecular profiling of RCC and the discovery of genomic and proteotranscriptomic factors that may contribute to disease trajectory. With the advent of multiple systemic therapies in mRCC in recent years, predictive biomarkers have become increasingly relevant in treatment selection. In this review, we discuss the existing staging systems and prognostic models in mRCC. We also highlight various promising molecular biomarkers according to the subtypes of RCC and explore their integration into the traditional prognostic models. In addition, we discuss emerging predictive biomarkers in the era of immuno-oncology. Lastly, we explore future directions with a focus on liquid biopsies and composite biomarkers.