Proteomics methods, based on liquid chromatography and tandem mass spectrometry, produce large "shotgun" proteomes that are most appropriately compared not at the level of differentially expressed proteins only but at the more comprehensive level of biological networks and pathways. This is now possible with the emergence of functional annotation databases and tools, databases of canonical pathways and molecular interactions and computational text mining tools. Here, we used shotgun proteomics, and the differential proteomics modeling functionalities available in the Pathwaystudio network modeling program to define the cell physiology of Hodgkin's disease antigen-overexpressing (CD30 (hi)) CD4 (+) T cell lymphomas using the unique Marek's disease (MD) natural animal model. CD30 (hi) lymphoma cells have characteristics of activated T cells but are also fundamentally different from their nontransformed healthy counterparts. We compared the cell physiology of naïve, superantigen-activated and MD-transformed CD4 (+) T cell proteomes. While the superantigen-activated cells had signaling pathways associated with cell activation, inflammation, proliferation and cell death, the MD-transformed cells had growth factor, cytokine, adhesion, and transcription factor signaling responses associated with oncogenicity, cell proliferation, angiogenesis, motility, and metastasis.