Tumor heterogeneity underlies therapeutic resistance and tumor progression but quantifying and addressing it remains challenging. In their study on page 1674, So and colleagues show that DNA methyltransferase 3B (DNMT3B) protein is heterogeneously expressed in primary tumors from triple-negative breast cancer (TNBC) patients and TNBC mouse models. The cover depicts an immunohistochemical (IHC) image of an orthotopic primary tumor in which DNMT3B-high cells are stained with green fluorescent protein, DNMT3B-low cells are stained with red fluorescent protein, vimentin is marked with yellow fluorescence, and DAPI-stained nuclei fluoresce blue. Further IHC and flow cytometry analyses revealed DNMT3B-high cells are more abundant in circulation and lung metastases than DNMT3B-low counterparts, demonstrating that DNMT3B promotes metastasis. Abrogating DNMT3B induction and enzymatic activity using Celecoxib and 5-azacytidine, respectively, alongside other chemotherapies decrease pulmonary metastasis, suggesting that targeting effectors of tumor heterogeneity augments chemotherapeutic efficacy. This article is also Highlighted on page 1589.