Acquired resistance to cDDP (cisplatin, a cytostatic drug) appears to be a multi-factorial process and is likely to be the result of an altered gene expression pattern. The goal of this study is to profile such an expression pattern by identifying genes whose mRNA levels are differentially expressed in cDDP-sensitive cells (UMSCC10b) versus its resistant variant (UMSCC10b/Pt-S15). Using suppressive subtraction hybridization (SSH) and cDNA expression array technology, 400 clones were randomly selected and differentially screened using cDNA arrays, resulting in 2 different cDNA libraries: a UP library with 51 cDNA fragments (upregulated in cDDP-resistant variants) and a DOWN library with 16 fragments (downregulated in the cDDP-resistant variants). We positively identified 87% of the cDNA fragments in GenBank. To identify those mRNAs whose change in expression level was most closely linked to the degree of cDDP resistance, cDNA probes obtained from the parental UMSCC10b cells and four resistant UMSCC10b variants with different levels of resistance (two- to sixfold) were used to hybridize cDNA arrays containing the UP and DOWN libraries. Among the mRNAs analysed, only one demonstrated a clear association with the magnitude of resistance (cytochrome oxidase mRNA), all the other mRNAs showed increased levels in resistant variants, but these increases varied only slightly at the various levels of resistance. Given the function of most of the identified genes (encoding cytochrome oxidase, ribosomal protein 28S, elongation factor 1a, glyceraldehyde phosphate dehydrogenase, a-enolase, stathmin and HSP70), it appears that they mainly represent genetic downstream events, thus describing a resistant phenotype with increased level of metabolism, proliferation rate, protein synthesis and cytoskeletal function as well as activated signalling pathways.