Carbon monoxide (CO) at therapeutic concentrations induces growth arrest of lung and prostate cancer cell lines and tumors. CO is generated endogenously as a bioactive signaling molecule by the cytoprotective gene heme oxygenase-1 (HO-1). In cancer cells, HO-1 activity, and thus endogenous CO levels, is decreased and can be rescued by delivery of exogenous CO. Astonishingly, CO sensitizes cancer cells to chemotherapeutic agents while simultaneously protecting normal cells from genotoxin-induced cell death. The mechanism of CO involves its propensity to bind to heme-containing oxidases in mitochondria. Shown here are prostate cancer cells (PC3) exposed to CO in the presence of the genotoxin doxorubicin, which resulted in a dramatic shift in mitochondrial membrane potential and metabolic collapse driven by an anti-Warburg effect. Using MitoTracker Red CMXRos staining (red), which fluoresces when a cell is actively respiring, Wegiel and colleagues observed that CO decreased respiration and mitochondrial membrane potential, indicative of mitochondrial failure. Nuclei were stained with Hoechst (blue). For details, see article by Wegiel and colleagues on page 7009.