Metazoans use a handful of highly conserved signaling pathways to create a signaling backbone that governs development. How these few signals have such a versatile action likely depends upon the larger-scale network they form through integration, as exemplified by cross-talk between the Notch and receptor tyrosine kinase (RTK) pathways. We examined the transcriptional output of Notch–RTK cross-talk duringDrosophiladevelopment and present in vivo data supporting a role for selected mutually regulated genes in signal integration. Interestingly, Notch–RTK integration did not lead to general antagonism of either pathway, as is commonly believed. Instead, integration had a combinatorial effect on specific cross-regulated targets, which unexpectedly included numerous core components of the RTK and other major signaling pathways (TGF-β, Hh, Jak/Stat, nuclear receptor and Wnt). We find the majority of Ras-responsive genes are also Notch-responsive, suggesting Notch may function to specify the response to Ras activation.