In spite of the expensive preclinical testing, the consistent failure to translate many promising targeted drugs from the laboratory bench to the clinic raises the question of whether the single-pathway drug-discovery strategies offer the correct perspective. As revealed by network biology, cancers harbor robust biological networks that are inherently resistant to changes, such as those induced by drugs with very narrow mechanisms of action. Therefore, network pharmacology strategies, the treatment of cancer by modulating more than one target, are needed. Different promiscuous approaches targeting multiple avenues within cancer-associated networks, such as the pleiotropic natural products, are emerging. Nevertheless, there is a long way before such 'proof-of-concept strategies' can be successfully applied in the clinical setting. This article provides a perspective on the current challenges in drug discovery, the reasons for high failure rates and how network pharmacology can aid the successful design of agents against cancer.