Two-dimensional gel electrophoresis coupled to protein microarray analysis was used to examine for the first time the molecular mechanisms of grapevine habituation ( Vitis vinifera L., cv. Limberger) at both the proteome and the interactome level. The examination of 2-D maps derived from control and habituated cell cultures revealed the presence of 55 protein spots displaying a differential expression pattern. Using computational prediction methods, fundamental differences were found between eukaryotic interactomes. It was confirmed that all the predicted protein family interactomes (the full set of protein family interactions within a proteome) of six species are scale-free networks, and that they share a small core network comprising 16 protein families related to indispensable cellular functions predominantly involved in pathogenesis, apoptosis and plant tumorigenesis. There is molecular evidence suggesting that grapevine cells which have become habituated for one or more essential factors originated from heritable alterations in the pattern of gene expression and that they can, therefore, be used as a model for the study of cell differentiation and/or neoplastic transformation.