The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway is a key player in animal development and physiology. Although it functions in a variety of processes, the net output of JAK-STAT signalling depends on its spatiotemporal activation, as well as extensive crosstalk with other signalling pathways. Drosophila, with its relatively simple signal transduction pathways and plethora of genetic analysis tools, is an ideal system for dissecting JAK-STAT signalling interactions. In this review, we explore studies in Drosophila revealing that JAK-STAT signalling lies at the nexus of a complex network of interlinked pathways, including epidermal growth factor receptor (EGFR), c-Jun N-terminal kinase (JNK), Notch, Insulin, Hippo, bone morphogenetic protein (BMP), Hedgehog (Hh) and Wingless (Wg). These pathways can synergise with or antagonise one another to produce a variety of outcomes. Given the conserved nature of signal transduction pathways, we conclude with our perspective on the implication of JAK-STAT signalling dysregulation in human diseases, and how studies in Drosophila have the potential to inform and influence clinical research.