Clear cell renal cell carcinoma (ccRCC) represents the most common subtype of renal cell carcinoma (RCC). In spite of recent advances in the treatment armamentarium and outcomes with the combined use of immune checkpoint and angiogenesis inhibitors, prediction of responses and selection of patients remain a challenge. This is a case of ccRCC with recurrence to the liver 1 year following right radical nephrectomy, who rapidly progressed on frontline therapy with axitinib/pembrolizumab. The clinical course and targeted tumor sequencing findings are discussed. In addition to established clinical prognostication in RCC, several surrogate markers of efficacy or/and resistance have been proposed for immunotherapy or/and anti-angiogenic therapy. Since the majority of patients will still progress after these combinations, it is becoming increasingly important to develop robust predictive biomarkers to guide patient selection and sequencing of targeted therapies.