TGF-beta can act as both a potent tumour promoter and tumour suppressor in a context dependent fashion. During cancer progression tumour cells can modify their response to TGF-beta from anti-proliferative to pro-tumourigenic whereby they can utilise TGF-beta to promote tumour cell proliferation, survival, motility, invasion, intravasation, extravasation, metastatic colonisation and promotion of cancer stem cell straits. Cancer stem cells (CSCs) represent defined subsets of cells within tumours that are capable of sustaining tumour growth, allowing spread and re-initiation at distant metastatic sites and therefore represent a key target for effective cancer therapy. Whole genome gene regulation studies coupled with siRNA screening has enabled us to identify a core set of novel TGF-beta target genes required for TGF-beta to promote CSC and metastatic traits in squamous cell carcinoma and breast cancer cells. These targets include new molecular entities and genes that link TGF-beta signalling to cell metabolism. Bioinformatic analyses indicate that these genes may play important roles in several malignancies including breast, lung, ovarian, liver, brain and skin cancers. We will employ a combinatorial approach both in vitro and in vivo employing biochemical, cell biology, microscopy, gene expression profiling, proteomics, metabolomics, bioinformatics and xenograft techniques coupled with clinical investigation of human tumour tissue to determine the function and regulation of these genes in cancer stem cells and metastasis. These studies should provide novel mechanistic insight into the regulation of cancer and CSCs and lead to possible exploitation of these findings for cancer therapy.