The study addresses the complex regulation of HSCs, highlighting p21’s multifunctional nature beyond cell cycle control. Through the use of p21-tdTomato mice, researchers differentiate between p21-tdT+ and p21-tdT− HSCs. Results show that p21-tdT+ HSCs display increased self-renewal and reconstitution abilities. Zbtb18, upregulated in p21-tdT+ HSCs, is crucial for their repopulation capability. p21 interacts with ZBTB18 to suppress cKit, influencing HSC self-renewal.