Y-box binding protein-1 (YB-1) is overexpressed in breast and other cancers, is associated with cancer recurrence, and confers poor prognosis. In the present study, To and colleagues report that activated phospho-YB-1^S102 induces the expression of CD44 and CD49f, eliciting hallmarks of tumor-initiating cells (TIC) behavior including mammosphere formation, self-renewal, and drug resistance. In the SUM 149 breast cancer model, the authors find that phospho-YB-1^S102 (green) colocalizes with high CD44 expression (red) in a subset of cells, and that this cell subpopulation exhibits enhanced TIC-associated properties. Nuclei are marked with DAPI staining (blue). For details, see the article by To and colleagues on page 2840 of this issue.