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To date, cancer stem cell (CSC) markers have been elucidated largely using population methods such as bulk RNA-sequencing, which may fail to convey CSC heterogeneity and subtypes. To facilitate CSC identification at single-cell resolution in colorectal cancer, Lin and colleagues performed single-cell RNA-sequencing using primary colorectal cancer tumors, colorectal cancer liver metastases, and normal colon and liver tissues. The authors found that canonical CSC marker expression was heterogeneous among epithelial cells, demonstrating that individual markers are insufficient for CSC identification. Gene expression analysis within the epithelial compartment enabled “gold standard” CSC detection, and the authors used the top 50 most highly expressed genes in these cells relative to non-CSC to construct a single-cell stemness signature (SCS_sig). SCS_sig expression was elevated in tumor tissues and CSC and correlated negatively with colorectal cancer patient disease-free survival. The SCS_sig also displayed bimodal expression patterns in normal tissues while presenting more continuous expression patterns...