Cyclin-dependent kinase-4 (CDK4) is a protein-serine kinase involved in the cell cycle. It is essential for the G1- to S-phase transition during the cell cycle and its expression is primarily controlled at the transcriptional level. CCND1- CDK4 axis is not only critical in glial tumor cells but also in stromal-derived cells in the surrounding tumor microenvironment that are vital to sustaining tumor outgrowth. CDK4 is highly expressed in highly differentiated and dedifferentiated liposarcomas but rarely expressed in other benign liposarcomas and other sarcomas. CDK4 and MDM2 combined to differentiate between highly differentiated liposarcoma (+), dedifferentiated liposarcoma (+), and myxoid liposarcoma, pleomorphic liposarcoma, spindle lipoma, pleomorphic lipoma, and other high-grade sarcomas.