Acute Myeloid Leukaemia (AML) is an aggressive disease characterised by low overall survival (<25 % at 5 years) and an extremely high relapse rate. The current mainstay therapeutic strategy described as “3+7”, administering daunrubicin and cytarabine (ara-C) in combination, is ineffective in 50–60 % of patients. New therapeutic strategies focusing on combination therapy that are effective against severe and resistant AML, with low toxicity to healthy haematopoietic cells, are urgently needed. Potential mechanisms of therapy resistance include over-expression of key regulators of apoptosis, such as members of the Inhibitors of Apoptosis Protein (IAP) family. Natural inhibitors for these proteins exist, termed second mitochondria-derived activator of caspases, or SMAC, and clinical mimetics have been developed showing anticancer potential, for example birinapant. We have generated murine models of leukaemia that recapitulate human disease and offer a system to study therapeutic strategies in vitro and in vivo. These models differ in their response to Smac-mimetic treatment, with some tumors being resistant to birinapant alone therapy. Thus, we decided to investigate whether birinapant could be therapeutically combined with other clinically relevant compounds to induce potent leukaemic cancer cell death. A High Throughput Screen of >5,700 clinically relevant compounds was conducted in birinapant resistant human and murine leukaemic cell lines. Twelve top hit compounds ranging greatly in their targets of action and clinical application were discovered that show synergistic killing in combination with Birinapant at low concentration. These novel combinations offer an exciting potential as anticancer therapies utilising diverse signaling pathways previously undescribed.