A better understanding of the aetiopathogenetic molecular targets in renal cell carcinoma (RCC) and the subsequent advent of targeted therapeutic agents have greatly improved the management and prognosis of RCC and patient survival. However, optimising therapeutic outcomes through appropriate sequential or combination therapy remains a challenge. Our 45-year-old male patient presented with metastatic renal cell carcinoma (mRCC); we effectively managed his aggressive, progressive disease across six lines of treatment, including sequential monotherapy and combination therapy, with targeted agents like sunitinib, everolimus, sorafenib, temsirolimus, and bevacizumab, resulting in a >48-month survival. Appropriate therapy with agents that have non-overlapping target profiles minimised treatment-related toxicities, enabling our patient to tolerate therapy at full doses. This case represents a good example of a significant clinical benefit of targeted therapy beyond the fourth line in mRCC. The survival and prognosis of mRCC patients may thus be significantly improved with the suitable use of newer targeted agents.