Primary tumor growth induces host tissue responses that are believed to support and promote tumor progression. Identification of the molecular characteristics of the tumor microenvironment and a deeper knowledge of its crosstalk with tumor cells may therefore be crucial for improving our understanding of the processes implicated in cancer progression, for discovering potential therapeutic targets, and for finding a stromal signature that may predict clinical outcome. To selectively address stromal gene expression changes during cancer progression, oligo-based Affymetrix microarray technology was used to analyze laser-microdissected stromal cells derived from invasive human breast and prostate carcinoma in comparison to their normal counterparts. Statistical analysis of the gene expression profile of breast and prostate stroma revealed genes differentially expressed in tumor stroma compared to normal stroma together with genes common to the stromal reaction in both tumor types. Several up and downregulated genes were validated by quantitative real-time RT-PCR and one common upregulated gene, periostin (POSTN), was validated by immunohistochemistry. The tumor-specific stromal genes as well as common stromal genes were observed to cluster breast and prostate cancer patients into two groups with statistically different clinical outcome. Univariate Cox analysis identified the genes whose expression level was most strongly associated with patient survival. Taken together, these observations provide evidence of the implication of the tumor microenvironment in tumor progression and its survival-predictive value.