The serine/threonine kinase Akt/PKB promotes cancer cell growth and invasion through several downstream targets. Identification of novel substrates may provide new avenues for therapeutic intervention. Our study shows that Akt phosphorylates the cancer‐related transcription factor Runx2 resulting in stimulated DNA binding of the purified recombinant protein in vitro. Pharmacological inhibition of the PI3K/Akt pathway in breast cancer cells reduces DNA‐binding activity of Runx2 with concomitant reduction in the expression of metastasis‐related Runx2 target genes. Akt phosphorylates Runx2 at three critical residues within the runt DNA‐binding domain to enhance its in vivo genomic interactions with a target gene promoter, MMP13. Mutation of these three phosphorylation sites reduces Runx2 DNA‐binding activity. However, Akt signaling does not appear to interefere with CBFβ‐Runx2 interactions. Consequently, expression of multiple metastasis‐related genes is decreased and Runx2‐mediated cell invasion is supressed. Thus, our work identifies Runx2 as a novel and important downstream mediator of the PI3K/Akt pathway that is linked to metastatic properties of breast cancer cells. J. Cell. Physiol. 228: 1784–1792, 2013. © 2013 Wiley Periodicals, Inc.