Prognosis for brain cancer, whether primary or metastasis, remains poor, even with advances in treatment for other cancers, due to the limited number of drugs that cross the blood brain barrier (BBB). While methods of overcoming this barrier have been developed and employed with current treatment options, the majority are highly invasive and non-specific, leading to neurotoxic side effects. A novel approach to address these issues is development of therapeutics targeting receptor mediated transport mechanisms on the BBB endothelial cell membranes. We have developed aptamers as targeted delivery agents that cross the BBB. Numerous studies have demonstrated that, despite theoretical implications of rapid renal clearance, nuclease degradation, and electrostatic repulsion, aptamers are effective agents for drug delivery. We have combined two aptamers for the targeted delivery of chemotherapeutics to brain metastases which cross the BBB and specifically target cancer cells in the brain. Using this approach, we intercalated doxorubicin into this bifunctional aptamer targeting the transferrin receptor on the BBB and epithelial cell adhesion molecule on the metastatic cells. The ability of the doxorubicin loaded aptamer to transcytose the BBB and selectively deliver the drug to epithelial cell adhesion molecule-positive tumours was evaluated in an in vitro model and confirmed in vivo. We showed co-localised aptamer and doxorubicin fluorescent signals are clearly detectable within the brain lesions 75 minutes post administration. Following a short treatment schedule, brain metastases decreased following bifunctional-aptamer-doxorubicin treatment, as compared to control or free drug. As well, metastases decreased in bone and ovaries. Collectively, these results demonstrate that through intercalation of a cytotoxic drug into the bifunctional aptamer, a therapeutic delivery vehicle can be developed for the specific targeting of epithelial cell adhesion molecule-positive brain and systemic metastases. We are now investigating this technology against primary brain cancers with different aptamers targeting other cell surface receptors.