Regardless of the diverse modes of treatment, the prognosis and clinical response of AML (Acute myeloid leukemia) remain low as the conventional modes of treatment, including cytarabine and anthracycline have their limitations. Moreover, chemotherapy-induced cytotoxicity triggers the remission, thus most of AML patients succumb to relapse. The monotherapy is also not helping much due to the rapid growth of AML, while an insufficient period of time is a major barrier in immunotherapy. Therefore, the current focus has been on combination therapy, with different agents, possibly because chemotherapy for AML is associated with infection, inflammation and could be rather toxic when combined with immunotherapy. Thus, there is the utmost need for developing a new approach and treatment for AML. Recent therapies focus on various novel signaling pathways and proteins that promote the survival of cancer cells in AML patients. This single or combinatorial approach may be more effective with less harmful effects. In this context, here we are discussing the role of PI3K/AKT/mTOR pathway in the survival of malignant cells as a potential target to combat relapse in AML patients. Accordingly, the therapeutic agents with a new class of inhibitors for plausible approaches to treat the patients with relapsed or refractory AML diseases could be advocated.