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Simple Summary: The TP53 tumor suppressor gene, the guardian of the genome, is mutated or has an inactive pathway in most chemo-resistant tumors. Most studies focus on the role of mutated TP53 in tumors. In this review, we discuss the role of p53 pathway alterations in renal cell carcinoma, one of the most chemo-resistant tumors that require clinical and resolutive approaches. The TP53 tumor suppressor gene is known as the guardian of the genome, playing a pivotal role in controlling genome integrity, and its functions are lost in more than 50% of human tumors due to somatic mutations. This percentage rises to 90% if mutations and alterations in the genes that code for regulators of p53 stability and activity are taken into account. Renal cell carcinoma (RCC) is a clear example of cancer that despite having a wild-type p53 shows poor prognosis because of the high rate of resistance to radiotherapy or chemotherapy, which leads to recurrence, metastasis and death. Remarkably, the fact that p53 is poorly mutated does not mean that it is functionally active, and increasing experimental evidences have demonstrated this. Therefore, RCC represents an extraordinary example of the importance of p53 pathway alterations in therapy resistance. The search for novel molecular biomarkers involved in the pathways that regulate altered p53 in RCC is mandatory for improving early diagnosis, evaluating the prognosis and developing novel potential therapeutic targets for better RCC treatment. [ABSTRACT FROM AUTHOR]