The 2021 World Health Organization classification for brain tumors introduced several new entities and categories. Tumors of uncertain differentiation are a new subcategory that includes the intracranial mesenchymal tumor, FET-CREB fusion-positive; the CIC-rearranged sarcoma; and the Primary intracranial sarcoma, DICER1-mutant. A search was made in Pubmed and Google Scholar to include all articles with the term “uncertain differentiation”, “Mesenchymal, non-meningothelial”, “FET-CREB fusion positive”, “DICER1-mutant sarcoma” and “CIC-Rearranged sarcoma” in their title. These articles were reviewed to draft a concise review on this subject. This review on CNS non-meningothelial mesenchymal tumors is meant to provide an update with diagnostic, prognostic, and therapeutic implications. Tumors of uncertain differentiation include a variety of mesenchymal, non-meningothelial tumors that have distinct molecular characteristics and consequently behave in a very particular matter. Given that these tumors have been described only recently, there is still an important lack of information regarding the most appropriate treatment and prognosis.