Tks5 (tyrosine kinase substrate with 5 SH3 domains) is an adaptor protein which cooperates with Src tyrosine kinase to promote the formation of protease-enriched, actin-based projections known as invadopodia, which are utilized by invasive cancer cells to degrade the extracellular matrix (ECM). We previously identified a Src-Tks5-Nck pathway which promotes invadopodium formation and ECM proteolysis in melanoma and breast cancer cells. We therefore sought to investigate the significance of Tks5 expression in human cancers. This was undertaken retrospectively through an immunohistochemical evaluation in tissue microarray cores and through data mining of the public database, Oncomine. Here we showed that Tks5 was expressed at higher levels in the microarray cores of breast, colon, lung and prostate cancer tissues compared to the levels in normal tissues. Importantly, mining of Oncomine datasets revealed a strong correlation between Tks5 mRNA overexpression in a number of cancers with increased metastatic events and a poorer prognosis. Collectively, these findings suggest a clinical association of Tks5 expression in human cancers. It identifies the importance for further investigations in examining the full potential of Tks5 as a relevant prognostic marker in a select number of cancers which may have implications for future targeted therapies.