Engineering effective cancer therapeutics requires quantitative understanding of the intracellular protein networks that govern cell proliferation. Aberrant activation of either the Wnt signaling pathway or the epidermal growth factor (EGF) signaling pathway has been shown to drive hyperproliferation in a diverse range of cancer types. The key effector of the canonical Wnt signaling pathway is the intracellular protein β-catenin, which translocates to the nucleus and activates transcription of cell cycle genes upon stimulation with Wnt ligands. Recently, we demonstrated that EGF, a non-Wnt ligand, can activate transcription of cell-cycle genes by β-catenin in a non-tumorigenic cell system; here, we extend those results to a tumor cell system; in addition, we demonstrate that the canonical Wnt ligand Wnt 3a also activates transcription of β-catenin target genes with dynamics similar to those of EGF-mediated β-catenin signaling. Furthermore, we dissected the signaling network through which Wnt and EGF activate β-catenin. As expected, Wnt 3a functions through the canonical Wnt signaling mechanism; in contrast, EGF works via a novel mechanism that does not involve the stabilization of cytoplasmic β-catenin. Using a suite of pharmacological inhibitors, we have parsed the role of several signaling pathways in both EGF- and Wnt 3a-mediated induction of β-catenin transcriptional activity. These studies reveal that EGF and Wnt 3a utilize both common and distinct pathways to activate β-catenin signaling; taken together, these data suggest a model whereby two unrelated ligands, EGF and Wnt 3a, utilize overlapping yet distinct signaling pathways to impinge upon the transcprition target genes by β-catenin. This novel crosstalk between the canonical Wnt and EGF signaling pathways suggests a tightly coupled, quantitative synergy between these prominent oncogenic pathways.