Genomic instability is a characteristic of many human cancers. It has been well documented, utilizing endpoints such as karyotypic instability and gene amplification, that alterations in the tumor suppressor p53 are related to genomic instability at the chromosomal level. The p53 protein has been implicated in multiple cellular responses related to DNA damage, including apoptosis, cell cycle control and DNA replication, repair and transcription. Alterations in any of these processes could be related to increased genomic instability. We previously compared radiation-induced mutagenicity among human B lymphoblast cell lines with different p53 status, including p53-null cells (NH32), cells with wild-type p53 (TK6) and cells with mutated p53 (WTK1). The results showed that at the TK1 locus p53-null cells had equivalent background mutation frequencies and were approximately as mutable as TK6, whereas WTK1 were much more sensitive to spontaneously arising and radiation-induced mutation. These results indicated that the lack of wild-type p53 does not lead to increased mutability. In this study, to explore further how p53 is involved in regulating mutational processes, we used 7K complementary DNA microarrays to compare the patterns of gene expression between TK6 and NH32 cells following irradiation. Total RNA was extracted 3, 6, and 24 h after irradiation with 10-Gy X-rays. Our preliminary results indicated that irradiation resulted in more genes being upregulated than downregulated in human lymphoblast cells regardless of their p53 status. Furthermore, cluster analyses of gene expression profiles in TK6 and NH32 revealed different patterns. In TK6 radiation-induced p53-related responses showed a rapid induction (higher at 3 and 6 h after irradiation than at 24 h), whereas in NH32 radiation-induced p53-unrelated responses showed different kinetics (higher at 3 and 24 h after irradiation than at 6 h).