Cancer is a complex disease resulting from alterations of multiple signaling networks. Cancer networks have been identified as scale-free networks and may contain a functionally important key player called a hub that is linked to a large number of interactors. Since a hub can serve as a biological marker in a given network, targeting the hub could be an effective strategy for enhancing the efficacy of cancer treatment. Chemotherapies and radiotherapies are generally used to treat tumors not amenable to resection, and target single or multiple molecules associated with hubs. However, these therapies may unexpectedly induce the resistance of cancer cells to drugs and radiation. Cancer cells can overcome therapy-induced damage via the activation of back-up signaling pathways and flexible modulation of affected networks. These activities are considered to be the main reasons for chemoresistance and radioresistance, and subsequent failure of cancer therapies. Much effort is required to identify the key molecules that control the modulation of signaling networks in response to drugs and radiation. Network-based therapy that affects network flexibility, including rewired network structures and hub molecules in these networks, could minimize the occurrence of side-effects and be a promising strategy for enhancing the therapeutic efficacy of cancer treatments. This review is intended to offer an overview of current research efforts including ones focused on cancer-associated complex networks, their modulation in response to cancer therapy, and further strategies targeting networks that may improve cancer treatment efficacy.