Renal cell carcinoma (RCC) is the prevalent form of kidney cancer in adults, with clear cell renal carcinoma (ccRCC) being the predominant subtype. While surgical resection remains the primary curative approach for localized RCC, a significant number of patients encounter disease relapse. The advent of targeted therapies, including tyrosine kinase inhibitors (TKI), mammalian target of rapamycin (mTOR) inhibitors, and immune checkpoint inhibitors, has revolutionized the treatment of metastatic RCC. However, despite therapeutic advancements, the emergence of resistance poses a significant challenge. Resistance mechanisms in RCC involve the disruption of hypoxia pathways, activation of the PI3K/AKT/mTOR pathway, and increased expression of alternate proangiogenic factors. Furthermore, the sequestration of TKI within lysosomes contributes to reduced drug effectiveness and development of resistance. Current research is focused on overcoming resistance by identifying predictive biomarkers for treatment efficacy, developing novel variations of existing therapies that target alternative signalling pathways, and exploring combination therapy approaches. The objective of this review article was to provide a comprehensive assessment of resistance mechanisms to systemic therapies and explore emerging treatment strategies for RCC.