Nowadays immune-based combinations are the standard first-line treatment for metastatic renal cell carcinoma and involve the use of either two immunotherapy agents or an immunotherapeutic drug associated with a tyrosine kinase inhibitor. Treatment-related toxicity is the primary cause of drug discontinuation or dose reduction. A thorough understanding of the prevention and management of adverse events of the immune-based combinations is critical to ensure the success of treatment. Endocrinological toxicities during treatment with immune-based combinations are frequent and often manageable. However, in some cases, diagnosis can be complex, and the treatment requires multidisciplinary discussion. In addition, it is often challenging to determine which agent in the combination is responsible for a specific toxicity. In this review, we analyze the evidence regarding treatment-related endocrinopathies in renal cell carcinoma first-line therapy. We also discuss monitoring strategies to diagnose endocrinological adverse events and provide some practical tools for their daily management.