Cancer stem cells (CSCs) may serve as the cellular seeds of tumor recurrence and metastasis, and they can be generated via epithelial-mesenchymal transitions (EMTs). Isolating pure populations of CSCs is difficult because EMT programs generate multiple alternative cell states, and phenotypic plasticity permits frequent interconversions between these states. Here, we used cell-surface expression of integrin β4 (ITGB4) to isolate highly enriched populations of human breast CSCs, and we identified the gene regulatory network operating in ITGB4+ CSCs. Specifically, we identified ΔNp63 and p73, the latter of which transactivates ΔNp63, as centrally important transcriptional regulators of quasi-mesenchymal CSCs that reside in an intermediate EMT state. We found that the transcriptional program controlled by ΔNp63 in CSCs is largely distinct from the one that it orchestrates in normal basal mammary stem cells and, instead, it more closely resembles a regenerative epithelial stem cell response to wounding. Moreover, quasi-mesenchymal CSCs repurpose this program to drive metastatic colonization via autocrine EGFR signaling. Display omitted •ΔNp63 and p73 maintain residence in the quasi-mesenchymal breast CSC state•ΔNp63 and p73 are required for the post-extravasation proliferation of CSCs•ΔNp63 controls distinct transcriptional programs in CSCs and normal basal SCs•Quasi-mesenchymal CSCs use autocrine EGFR signaling to enable metastatic colonization Quasi-mesenchymal cancer stem cells (CSCs) are known to be highly metastatic. Lambert et al. demonstrate that ΔNp63 and p73 are key regulators of the quasi-mesenchymal CSC state. They show that these transcription factors control a regenerate epithelial stem cell program that drives metastatic colonization.