The cyclin-dependent kinase 4 (CDK4) gene is located in the chromosomal region 12q14.1, ~10 Mb centromeric to the murine double minute (MDM2) gene and is frequently coamplified with MDM2 in different malignancies. In a complex with cyclin D1 (CCND1), the CDK4 encoded serine/threonine kinase phosphorylates the retinoblastoma protein 1 (RB1) which in turn leads to the release of the EF2 transcription factor and subsequently to an upregulation of genes which are required for progression through the S-, G2-, and M-phases of the cell cycle. Due to amplification of the respective chromosomal region, CDK4 is overexpressed in many human tumors such as soft tissue sarcomas, osteosarcomas (OS), and gliomas. In glioblastomas, the lack of amplification of several genes like CDK4 was recognized to be associated with a longer survival time. In OS, coamplification of MDM2 and CDK4, located in two discontinuous regions, occurs frequently in parosteal OS and less often in classical high-grade OS. Although MDM2/CDK4 coamplification is not restricted to atypical lipomatous tumors/well-differentiated liposarcomas (ALT/ WDLPS) and dedifferentiated liposarcomas (DDLPS), its detection is a strong criterion for distinguishing these tumor types from other undifferentiated sarcomas and even from carcinomas and lymphomas.