Notch signaling controls a wide range of cell fate decisions during development and disease via synergistic interactions with other signaling pathways. We performed a genome-wide genetic screen in Drosophila and uncovered a highly complex Notch-dependent genetic circuitry that profoundly affects proliferation and consequently hyperplasia. We further examined two novel synergistic relationships, between Notch and either of the non-receptor tyrosine kinases Src42A and Src64B, and between Notch and the transcription factor Mef2. Both interactions promote hyperplasia and tissue disorganization, largely via activation of the JNK pathway, indicating that there are commonalities within the Notch-dependent proliferation circuitry; however, they differ in how they access and interpret the JNK signal. Most notably, whereas Notch-Src causes high levels of apoptosis, Notch-Mef2 does not display this phenotype, thus resulting in a comparatively higher degree of hyperplasia. We examined differential targets of the two synergies to identify downstream anti- or pro-apoptotic factors in Notch-Mef2 or Notch-Src respectively, and identified the transcription factor disco as a potential suppressor of apoptosis in Notch-Mef2 tissues. These findings underscore the complexity and specificity of the Notch signaling network and have potential implications for Notch-related cancers.