Circulating tumor cells (CTCs) from breast cancer patients were cultured to form mammospheres which exhibit stem-like properties. The mammospheres and total CTCs were tested for chemosensitivity to various drugs. Mammospheres were found to be significantly more chemoresistant than total CTCs. Salinomycin and curcumin showed high efficacy against mammospheres, with salinomycin destroying nearly all cells. The results demonstrate that stem-like CTCs circulating in blood are more resistant to chemotherapy than other CTCs, and salinomycin is a promising therapeutic for targeting chemoresistant tumor cells.