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Simple Summary: Leukemic cells show differential sensitivity to apoptosis induction by the clinically relevant drug hydroxyurea. Since resistance to hydroxyurea can pose a therapeutic problem, we searched for mechanisms that protect such cells from the toxic effects of hydroxyurea. We used proteomics followed by mass spectrometry to accomplish this task and noted a loss of the RAF1 kinase in cells that are killed by hydroxyurea. Pharmacological inhibition of RAF1 and its target BCL-XL show that these proteins suppress apoptosis induction. Furthermore, inhibition of their upstream regulators BCR-ABL1 (in chronic myeloid leukemia cells) and FLT3-ITD (in acute myeloid leukemia cells) plus hydroxyurea produced favorable results. This approach may benefit patients that are not successfully treated with tyrosine kinase inhibitors. Taken together, we provide novel insights into strategies that eliminate chronic and acute myeloid leukemia cells with combinations of clinically established and currently tested pharmaceutical agents. The ribonucleotide reductase inhibitor hydroxyurea suppresses de novo dNTP synthesis and attenuates the hyperproliferation of leukemic blasts. Mechanisms that determine whether cells undergo apoptosis in response to hydroxyurea are ill-defined. We used unbiased proteomics to uncover which pathways control the transition of the hydroxyurea-induced replication stress into an apoptotic program in chronic and acute myeloid leukemia cells. We noted a decrease in the serine/threonine kinase RAF1/c-RAF in cells that undergo apoptosis in response to clinically relevant doses of hydroxyurea. Using the RAF inhibitor LY3009120, we show that RAF activity determines the sensitivity of leukemic cells toward hydroxyurea. We further disclose that pharmacological inhibition of the RAF downstream target BCL-XL with the drug navitoclax and RNAi combine favorably with hydroxyurea against leukemic cells. BCR-ABL1 and hyperactive FLT3 are tyrosine kinases that causally contribute to the development of leukemia and induce RAF1 and BCL-XL. Accordingly, the ABL inhibitor imatinib and the FLT3 inhibitor quizartinib sensitize leukemic cells to pro-apoptotic effects of hydroxyurea. Moreover, hydroxyurea and navitoclax kill leukemic cells with mutant FLT3 that are resistant to quizartinib. These data reveal cellular susceptibility factors toward hydroxyurea and how they can be exploited to eliminate difficult-to-treat leukemic cells with clinically relevant drug combinations. [ABSTRACT FROM AUTHOR]