Cyclin-dependent kinase 6 (CDK6), a D-type cyclin regulator, has aberrant expression in various kinds of malignancies, including T-cell acute lymphoblastic leukemia (T-ALL). This review highlights the importance of CDK6 as a common downstream mediator in both Notch- and PTENAKT-dependent T-cell malignancies. As a central molecular player linking extracellular signals to cell cycle machinery, CDK6 orchestrates network dynamics in normal versus cancerous cells. Albeit much remains to be exploited, CDK6 serves as a potential adjuvant therapeutic target in the Notch and PTEN-AKT subgroup of T-ALL.