Immune checkpoint blockade (ICB) therapy has emerged as a valuable treatment modality for previously treated advanced or metastatic endometrial cancer (EC) that is mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H), with impressive and durable response rates seen in a significant proportion of patients. Conversely, a substantial proportion of patients with dMMR/MSI-H EC will not derive benefit from these therapies. It is vitally important to understand the mechanisms behind these disparate responses, as a one-size-fits-all approach, even within the dMMR/MSI-H EC subgroup, cannot be employed. Responses to ICB therapy in mismatch repair proficient (pMMR) or microsatellite stable (MSS) EC have been disappointing, and ICB monotherapy in this setting has not shown efficacy. Additional disadvantages of ICB therapy for the management of EC include the following: a lack of more definitive biomarkers predictive of response; the potential for long-term toxicity, which can necessitate the need for lifelong hormone replacement; a risk of serious sequalae (e.g., colitis, insulin-dependent diabetes mellitus); and extensive financial cost. Caution is warranted when considering this class of therapeutics for patients with EC, as there are still unanswered questions regarding their optimal use.