Receptor tyrosine kinases and the signaling networks that they control contribute to cancer and resistance to therapies. Therefore, understanding these networks, how they vary within and among tumors and how they adapt to enable cancer cells to circumvent treatment, should lead to more effective therapeutic strategies in treating the diverse disease that is cancer. As Science Signaling highlights in this week's issue, systems biology and computational biology are shining light on these complex networks and enabling integration of diverse information about genetics, proteomics, and network activity to effectively predict therapeutic response and identify key components to target for intervention.