These cell populations have already diversified likely due to various reasons such as genetics, epigenetics and environmental influences, producing a tumor that is highly heterogeneous. This diversity, known as intratumoral heterogeneity, is commonly thought to be one of the key mechanisms for therapeutic failures. An additional layer of tumor complexity is provided by the normal cells. Their pathological potential is linked to a wide variety of tumor cell properties, many of which are driven by intercellular communication mechanisms. Our laboratory studies how information from cells is conveyed to other cells in the context of glioblastoma, a representative model of tumor heterogeneity, and how this process is manifested in phenotypic heterogeneity. We also use our new knowledge to better experimental model systems faithful to human tumors and to rationally design combination therapy. In sum, we confront the tumor complexity, with a focus on cell-cell communications, that needs to be integrated into future medicine, and the testimony is below.