Inhibiting two oncogenic targets is a proven effective approach for treating cancer, and multiple combinations of drugs have been TGA and FDA approved. 1 Here, we study the dual inhibitory effect of heat shock protein 90 (hsp90) and heat shock protein 70 (hsp70), two well-established oncogenic targets. When used as a single drug, current clinical hsp90 inhibitors induce over-expression of hsp90 and hsp70, both of which facilitate survival of the tumor and therefore make the inhibitors ineffective.2-4 Hsp70 inhibitors have shown promise, but only when used in conjunction with other therapies.5 This work develops a combination treatment that targets both hsp90 and hsp70 in order to overcome the induction of hsp90 and hsp70 when both of these targets are inhibited. We comprehensively evaluate the efficiency of three specific drug combinations, and investigate their mechanism of action when used as a combination therapy. Our data show that dual inhibiting hsp90 and hsp70 by small molecules has very strong or strong synergistic effect in killing HCT-116 human colon cancer cells and in inducing caspase 3/7-dependent apoptosis.