Immune checkpoint blockade (ICB) therapy has emerged as an important treatment modality in a subset of endometrial carcinomas (ECs). However, these agents are not efficacious as monotherapy in the majority of ECs, underscoring the need to identify molecular signatures that better predict for response, and to devise rational combination therapeutic approaches that harness the chief oncogenic drivers in the various phenotypes of this heterogenous disease. Optimizing patient selection for ICB therapy is critical, for in addition to the financial burden associated with these therapies, they also pose a risk of serious adverse events in a significant minority of patients. Based on available data, it is clear that a one-size-fits-all approach for ICB therapy cannot be employed in the management of EC.