We have shown that circulating invasive cancer stem cells (cCSC) in the blood are the root of metastasis and distinct from their non-invasive counterparts in the primary tumour. As most patients with advanced cancer eventually succumb from metastatic spread of the disease, it is of crucial importance to understand the distinct biology of cCSC and direct efforts for finding new therapies against this particular cell population. However, their prospective isolation from the blood is technically challenging. Rare cCSC have to be detected among all blood cells and also separated from non-tumourigenic circulating cancer cells. Furthermore, their in vivo tumourigenicity as a defining feature of CSC must be demonstrated. To meet these criteria, we have developed a lab-on-a-chip microfluidic system based on immunomagnetic depletion of non-relevant blood cells followed by separation of cells according of their distinct physical characteristics. The efficiency of the system will has be validated using state-of-the-art in vivo mouse models for primary human cancers allowing the prospective isolation of circulating tumourigenic cells. While the specific detection of these circulating CSC can be used as a diagnostic tool for staging and monitoring treatment response, their prospective isolation from each individual patient provides a unique opportunity for tailoring therapies according to the features of individual cCSC.