Myxoid pleomorphic liposarcoma (MPLPS) is an exceedingly rare and recently recognized adipocytic neoplasm that primarily occurs in children and young adults and shows a strong predilection for the mediastinum. Clinically, MPLPS demonstrates aggressive behavior and exhibits a high propensity for systemic spread and a worse overall survival. Some cases have been associated with Li-Fraumeni syndrome. Histologically, MPLPS is composed of a variable mixture of myxoid and pleomorphic liposarcoma-like components. Immunohistochemically, the tumor cells show diffuse expression of CD34 and p16 and loss of nuclear RB expression. MPLPS lacks DNA damage inducible transcript 3 (DDIT3) rearrangements and MDM2 proto-oncogene (MDM2) amplifications but shows tumor protein p53 (TP53) mutations and RB transcriptional co-repressor 1 (RB1) deletions. Moreover, recent studies have demonstrated that the most consistent molecular feature of MPLPS is genome-wide loss of heterozygosity. Surgical excision with negative margins is the mainstay of treatment for localized MPLPS. The treatment of advanced/metastatic MPLPS still poses a huge therapeutic challenge. This review provides information about the clinicoradiological features, pathogenesis, histopathology, and management currently available for MPLPS. In addition, we discuss the differential diagnosis of this novel entity.