Although silica has been ranked by IARC as a human carcinogen in certain occupational settings since 1997, there is still some dispute as to its carcinogenicity. The association between silica and cancer has been the subject of studies since 1982, and the lack of an animal model for silica-induced carcinogenesis suggests to some that there is no causal relationship between silica exposure and cancer. Our hypothesis is that silica carcinogenicity follows the two-hit hypothesis in humans, so that only silica exposure in susceptible individuals, or those with a predisposing genetic alteration, would result in cancer formation. To determine this, we utilized three cell lines with variable expression of p53, a cell cycle control gene commonly mutated in human cancers. The goal of this study was to determine the effect of exposure to freshly fractured silica compared to aged silica using a normal human cell line (HBEAS), a human adenocarcinoma cell line (H460) with altered p53 expression, and a non-small cell lung cancer cell line (H1299) deficient in p53. Cell cycle parameters showed an increase in aneuploidy in the cancer cell lines following exposure to silica as compared to normal cells. Microarray analysis found variability in expression patterns of genes involved in apoptosis (BCL6) and cell cycle arrest (PCNA) as well as DNA damage repair genes (ERCC3, RAD23A). Gene expression analysis has highlighted differences related to p53 expression in the three cell lines following exposure to silica. These results suggest a potential role for p53 in silica-induced carcinogenicity.