Acute Myeloid Leukaemia (AML) is characterised by low survival and high relapse rates. Therefore, new therapeutic strategies that combine better response rates with reduced toxicity are needed. Resistance to apoptosis is one of the hallmarks of AML, contributing to the development of chemo-resistance. One of potential mechanisms of drug resistance is over-expression of key regulators of apoptosis such as IAPs (Inhibitors of apoptosis). In our study, we focused on a Smac-Mimetic compound already in clinical trial, Birinapant, which mainly targets cIAP1. We generated different AML mouse models by retroviral infection of haematopoetic progenitor cells with oncogenic translocations that closely recapitulate the human disesae. We have identified various subtypes of AML with different sensitivity to Birinapant. By screening clinical drugs with and without Birinapant, we were able to identify novel clinical drug combinations that efficiently kill both sensitive and resistant AML. We successfully validated these drug combinations in vitro. In general, these drug combinations provide a potential novel treatment strategy for AML.