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Simple Summary: A several immunotherapy-based combinations regimen improved overall survival, and became the new first-line standard of care for metastatic clear cell renal cell carcinoma (mccRCC) patients. However, a subset of patients, approximatively 30 to 60%, are refractory to these therapies or develop a secondary acquired resistance. Currently no validated biomarkers are available in routine practice to adapt treatment strategies. Here, we summarize the potential biological biomarkers for immune checkpoint inhibitors that may have arisen from the studies of immune checkpoints. Renal cell carcinoma (RCC) represents around 2% of cancer-related deaths worldwide per year. RCC is an immunogenic malignancy, and treatment of metastatic RCC (mRCC) has greatly improved since the advent of the new immunotherapy agents, including immune checkpoint inhibitors (ICIs). However, it should be stressed that a large proportion of patients does not respond to these therapies. There is thus an urgent need to identify predictive biomarkers of efficacy or resistance associated with ICIs or ICI/Tyrosine kinase inhibitor (TKI) combinations; this is a major challenge to achieve precision medicine for mRCC in routine practice. To identify potential biomarkers, it is necessary to improve our knowledge on the biology of immune checkpoints. A lot of efforts have been made over the last decade in the field of immuno-oncology. We summarize here the main data obtained in this field when considering mRCC. As for clinical biomarkers, clinician and scientific experts of the domain are facing difficulties in identifying such molecular entities, probably due to the complexity of immuno-oncology and the constant adaptation of tumor cells to their changing environment. [ABSTRACT FROM AUTHOR]