Inhibition of CDK6 activity with the kinase inhibitor palbociclib inhibits proliferation of Ph⁺ ALL cells, but does not interfere with the functions of CDK6 as a transcriptional regulator. In contrast, targeted degradation of CDK6 with a bifunctional PROTAC degrader removes both catalytic and transcriptional CDK6 functions. RB, retinoblastoma tumor suppressor, Ub, ubiquitin. See the visual abstract in the online version of the article by De Dominici et al that begins on page 1560.