The development of targeted therapies with true specificity for cancer relies upon exploiting differences between cancerous and normal cells. Genetic and genomic alterations including somatic mutations, translocations, and amplifications have served as recent examples of how such differences can be exploited as effective drug targets. Small molecule inhibitors and monoclonal antibodies directed against the protein products of these genetic anomalies have led to cancer therapies with high specificity and relatively low toxicity. Recently, our group and others have demonstrated that somatic mutations in the PIK3CA gene occur at high frequency in breast and other cancers. Moreover, the majority of mutations occur at three hotspots, making these ideal targets for therapeutic development. Here we employed gene targeting to “knock in” PIK3CA mutations into human breast epithelial cells, to identify new therapeutic targets with high selectivity for mutant PIK3CA. Mutant PIK3CA knock in cells were capable of epidermal growth factor and mTOR independent cell proliferation that was associated with GSK3β phosphorylation. The GSK3β inhibitors lithium chloride and SB216763 selectively decreased the proliferation of human breast and colorectal cancer cell lines with oncogenic PIK3CA mutations, and led to a decrease in the GSK3β target gene CYCLIN D1. Oral treatment with lithium significantly inhibited the proliferation of HCT-116 colon cancer cells with mutant PIK3CA when grown as nude mouse xenografts, but did not demonstrate this effect in isogenic knock out HCT-116 cells containing only wild type PIK3CA. Our results suggest GSK3β is an important effector of mutant PIK3CA, and that lithium, an FDA approved therapy for bipolar disorders, has selective anti-neoplastic properties against cancers that harbor these mutations.