Acute Myeloid Leukaemia (AML) is an aggressive disease characterised by low overall survival (<25% at 5 years) and an extremely high relapse rate. Current mainstay therapies are ineffective in 50–60% of patients, therefore new combination therapies that are effective against refractory AML, with low toxicity to healthy haematopoietic cells, are urgently needed. Potential mechanisms of therapy resistance include overexpression of key regulators of apoptosis, such as members of the Inhibitor 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. Therefore, we conducted a high throughput screen of >5,700 clinically relevant compounds in combination with birinapant in resistant human and murine AML cell lines to investigate whether these combinations can induce potent leukaemic cancer cell death. Twelve top hit compounds were identified that synergistically kill leukaemic cells at low concentrations, with preliminary results suggesting combination mediated cell death is apoptotic in nature and dependent on TNF receptor 1, TNF and RIPK1. In vivo biosafety results for two compounds demonstrates combination therapy is tolerable and safe, with preliminary data suggesting combination therapy can significantly increase survival in a murine leukaemia model. Furthermore, we have identified biomarkers of response to treatment, increasing the probability of success for these combinations to progress through clinical trials and into the clinic. These novel combinations offer exciting potential as anticancer therapies utilising diverse signalling pathways previously undescribed.