The PI3K/Akt signaling network regulates cell growth and apoptosis, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. Recent studies suggest that PI3K/Akt signaling is frequently up-regulated in blast cells from AML patients and strongly contributes to proliferation, survival, and drug-resistance of these cells. Up-regulation of this network in AML may due to several reasons, including FLT3 and Ras activating mutations, increased levels of PI3K p110δ catalytic subunit, lack of PTEN lipid phosphatase expression, and autocrine production of growth factors. Small molecules designed to specifically target key components of this signal transduction network have been shown to induce apoptosis and/or increase conventional drug sensitivity of AML blasts in vitro. Therefore, these inhibitory molecules are being developed for clinical use either as single therapeutic agents or in combination with other forms of therapy. Nevertheless, PI3K/Akt blockade in vivo might have detrimental systemic side effects, given the multiple physiological roles played by this pathway, such as insulin-dependent glucose transport. Herein, we summarize our knowledge about PI3K/Akt signaling in AML and we highlight several pharmacological inhibitors which could be used in the future for treating this too often fatal hematological disorder.