It highlights the basic and clinical findings on the cyclin-dependent kinases 4 and 6 (CDK4/6) cell cycle regulatory pathway in the context of the precision medicine-based molecular profiles of the three most common types of pediatric and AYA sarcomas—osteosarcoma (OS), rhabdomyosarcoma (RMS), and Ewing sarcoma (EWS). This evidence concerns the gene CDK4 and sarcoma.