The S100 family is a group of small, calcium-binding proteins with at least 20 distinct members in humans. Several of these have been associated with cancer invasion or metastasis in recent studies. Transcriptional analysis of gene expression in a panel of lung cancer-derived cell lines identified S100A13 as being associated with a more aggressive invasive phenotype in vitro. Hierarchical clustering grouped this gene with several others that have established functional roles in this phenotype both in vitro and in vivo (ICAM1, CD34, EFNB2 and HGF) as well as genes involved in processes such as angiogenesis (TEM7, JAG2). Depletion of cellular S100A13 mRNA levels by RNAi in highly invasive lung cancer cell lines resulted in a 50-80% decrease in their invasive potential in an in vitro assay. This reduction could not be accounted for by reduced cellular proliferation. Conversely, transient overexpression of exogenous S100A13 in less invasive cell lines had no impact on invasive potential suggesting that upregulation of S100A13 expression alone is insufficient to induce the phenotype. We conclude that S100A13 is involved in but not capable of inducing invasion, since elevated S100A13 mRNA expression correlates with a more invasive phenotype and in vitro invasion can be inhibited by reduced S100A13 expression.