Cancer research has focused on the identification of molecular differences between cancerous and healthy cells. The emerging picture is overwhelmingly complex. Molecules out of many parallel signal transduction pathways are involved. Their activities appear to be controlled by multiple factors. The action of regulatory circuits, cross-talk between pathways and the non-linear reaction kinetics of biochemical processes complicate the understanding and prediction of the outcome of intracellular signaling. In addition, interactions between tumor and other cell types give rise to a complex supra-cellular communication network. If cancer is such a complex system, how can one ever predict the effect of a mutation in a particular gene on a functionality of the entire system? And, how should one go about identifying drug targets? Here, we argue that one aspect is to recognize, where the essence resides, i.e. recognize cancer as a Systems Biology disease. Then, more cancer biologists could become systems biologists aiming to provide answers to some of the above systemic questions. To this aim, they should integrate the available knowledge stemming from quantitative experimental results through mathematical models. Models that have contributed to the understanding of complex biological systems are discussed. We show that the architecture of a signaling network is important for determining the site at which an oncologist should intervene. Finally, we discuss the possibility of applying network-based drug design to cancer treatment and how rationalized therapies, such as the application of kinase inhibitors, may benefit from Systems Biology. © 2005 Elsevier Ireland Ltd. All rights reserved.