We compared the gene expression patterns of oxaliplatin-resistant cell lines with the patterns of their sensitive counterparts in an attempt to discover universal mechanisms that characterize resistant cells. Isogenic oxaliplatin-resistant variants of four ovarian carcinoma cell lines and one squamous cell carcinoma line were selected by repeated exposures of increasing concentrations of oxaliplatin (resistance levels ranged from 4-fold to 20-fold). We harvested RNA from all five pairs and assayed gene expression through hybridization to Affymetrix HuGeneFL arrays. Using global, unsupervised, two-way hierarchical clustering we observed that resistant cell lines clustered with their corresponding parental cell lines, indicating that the number of changes in gene expression leading to resistance are probably few and that these changes are diluted in the global gene expression profile of the entire cell. In addition, Venn diagram analysis revealed that very few genes were commonly up- or downregulated across all cell lines. However, employing a recently developed supervised clustering method that uses principal component analysis to extract groups of genes with maximal variance across cell lines, we found a small cluster of genes that were consistently differentially expressed in most but not all resistant cell lines. Although this group of genes contains some interesting members, it is unlikely that these genes are the sole determinants of oxaliplatin resistance. Finally, comparison of the numbers of differentially expressed genes from each pair that were associated with specific MeSH terms supported our conclusion that no common mechanism of resistance could be detected within the five resistant pairs.