Systemic chemotherapy is the main anticancer treatment for most kinds of clinically diagnosed solid tumors. However, the efficacy of anticancer drugs is often lower than expected or desired. Moreover, after a good initial reaction, the tumors often become non-responsive and resistant to the drugs. These impediments in anticancer therapy can be attributed to insufficient drug delivery to all tumor cells. If drug molecules are not able to reach all tumor cells in adequate quantities, they cannot evoke the desired effects. One of the barriers to effective intratumoral drug delivery is the complex, spatially and temporarily variable tumor microenvironment. We will discuss several aspects of the tumor environment as barriers to interstitial drug transport. We will also present the results of our cross-disciplinary efforts, which include multiscale mathematical modeling, laboratory experiments and medical image analysis techniques that we are developing to improve the effectiveness of anticancer chemotherapy. The use of medical images allows us to consider the specific properties of tumor cells, cell colonies and tumor microenvironments and holds promise for designing personalized treatments based on patients’ biopsies routinely collected for cancer diagnosis in clinics.