Signaling pathways in mammalian cells are assembled and regulated by a finely controlled network of protein-protein and protein-phospholipid interactions, mediated by dedicated signaling domains and their cognate binding motifs. The domain-based modular architecture of signaling proteins may have facilitated the evolution of complex biological systems, and can be exploited experimentally to generate synthetic signaling pathways and artificial mechanisms of autoregulation. Pathogenic proteins, such as those encoded by bacteria and viruses, frequently form ectopic signaling complexes to respecify cellular behavior. In a similar fashion, proteins expressed as a consequence of oncogenic fusions, mutations or amplifications can elicit ectopic protein-protein interactions that re-wire signaling pathways, in a fashion that promotes malignancy. Compounds that directly or indirectly reverse these aberrant interactions offer new possibilities for therapy in cancer.