Cancer patients increasingly benefit from personalized anti-cancer treatments. These treatments are mostly tailored to the tumor genetic makeup. Nevertheless, response is usually partial and resistance to treatment is common. We used cutting-edge technologies to screen for the effect of hundreds of tumor microenvironmental factors on the resistance to anti-cancer therapies. We found dozens of factors that can compromise the tumor’s initial response to treatment, and are currently following a few of these factors in vitro, in vivo and ex vivo. Our findings indicate that tailoring treatment to both tumor genetics and the individual’s tumor microenvironment is a promising approach.