FOXC1 dependencies develop as a consequence of dysregulated programs in cancer cells and affect clinical progression, therapeutic responsiveness and outcome often emerging to a level of dependence referred to as “transcriptional addiction.” Collectively, the elucidated mechanisms by which FOXC1 modulates aggressive cancer cell traits support our contention that FOXC1 is predominantly a transcriptional driver of cellular plasticity and a cancer stem cell phenotype. The gene discussed is FOXC1; the disease is cancer.