Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). In a screen for compounds down-regulating Mcl-1, we identified the kinase inhibitor, PIK-75, which demonstrates marked pro-apoptotic activity against AML stem and progenitor cells from a panel of 46 primary patient samples, including adverse cytogenetic risk, FLT3-ITD mutant and relapsed/refractory cases. PIK-75 induced a transient block in cyclin-dependent kinase 7 and 9 (Cdk7/9) activity leading to transcriptional suppression of MCL-1 and AML cell death. Importantly, concentrations of PIK-75 that promote apoptosis in primary human AML cells did not affect the survival of bone marrow progenitors from normal donors. In addition to inhibiting Cdk7/9, PIK-75 also targets the p110a isoform of phosphatidyl inositol 3-OH kinase (PI3K) and we show that dual inhibition of Cdk7/9 and PI3K is synergistic and necessary for optimal apoptosis of primary AML cells. PIK-75 killing was rapid (<6h), Bak-dependent and p53 independent. Importantly, PIK-75 treatment of mice engrafted with human AMLs significantly increased their median survival with no evidence of in vivo toxicity. Beyond AML, we also show that PIK-75 potently induces apoptosis in a panel of 16 cancer lines derived from multiple myeloma, brain and breast cancer. Our results identify a hitherto unrecognised alliance between PI3K and Cdk7/9 in promoting leukemic survival and show that dual inhibition of Cdk9 and PI3K by PIK-75 enhances apoptosis of AML cells. With limited efficacy demonstrated so far for PI3K and Cdk inhibitors in the clinic, future efforts to co-target PI3K:Akt and Cdk9:Mcl-1 with drugs such as PIK-75 in AML is warranted