Breast cancer cells with stem cell properties play an important role in tumor progression and thus are key targets for therapy. Here, we show that combined Bcl-2/Src inhibition synergize to deplete stem-like cells. While Src inhibition increases pro-apoptotic PUMA, we find that a significant amount interacts with Bcl-2 and Bcl-xL, promoting resistance to cell death. Consistent with this, the clinically-approved Bcl-2 selective drug venetoclax was sufficient to overcome resistance by preventing PUMA/Bcl-2 binding, enhancing apoptosis. This effect was specific to stem-like breast cancer cells as there was no effect on luminal or basal-like cell types. In contrast, the Mcl-1 inhibitor S63845 potently targeted basal-like, but not stem-like cells, highlighting dependency on distinct sentinel Bcl-2 family members. Our findings reveal Bcl-2/Src inhibition as a superior therapy to target stemness, providing a foundation for a potential personalized strategy to reduce breast cancer progression.