Synthetic biology as the discipline of reconstructing natural and designing novel biological systems is gaining increasing impact in signaling science. This review article provides insight into synthetic approaches for analyzing and synthesizing signaling processes starting with strategies into how natural and pathological signaling pathways can be reconstructed in an evolutionary distant host to study their topology and function while avoiding interference with the original host background. In the second part we integrate synthetic strategies in the rewiring of signaling systems at the nucleic acid and protein level to reprogram cellular functions for biotechnological applications. The last part focuses on synthetic inter-cell and inter-species signaling devices and their integration into synthetic ecosystems to study fundamental mechanisms governing the co-existence of species. We finally address current bottlenecks in the (re-)design of signaling pathways and discuss future directions in signaling-related synthetic biology. © 2010 The Royal Society of Chemistry.