Wnt signalling is a fundamentally important signalling pathway that regulates many aspects of metazoan development and is frequently dysregulated in cancer. Although many of the core components of the Wnt signalling pathway, such as β-catenin, have been extensively studied, the broad systems level responses of the mammalian cell to Wnt signalling are less well understood. In addition, the cell- or tissue-specific protein networks that modulate Wnt signalling in the diverse tissues or developmental stages in which it functions remain to be defined. To address these questions, we undertook a broad survey of the Wnt response in different human cell lines using both interaction and expression proteomics approaches. Our data reveal both similar and divergent responses of pathways and processes in the three cell-lines analyzed as well as a marked attenuation of the response to exogenous Wnt treatment in cells harbouring a stabilizing (activating) mutation of β-catenin. We also identify cell-type specific components of the Wnt signalling network and find that by integrating expression and interaction proteomics data a more complete description of the Wnt interaction network can be achieved. Finally, our results attest to the power of LC-MS/MS to reveal novel cellular responses in even relatively well studied biological pathways such as Wnt signalling.