The central role of phosphoinositide 3-kinase (PI3K) in tumor cell biology has led to extensive efforts to target PI3K and downstream kinases like AKT and mTOR in cancer treatment. However, clinical data show limited single-agent activity of PI3K/AKT/mTOR inhibitors at tolerable doses. An exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukemia, driven by both cell-intrinsic and extrinsic activities. This review discusses key challenges and opportunities for the clinical development of PI3K/AKT/mTOR inhibitors. It emphasizes the importance of patient selection, understanding immune modulation, and strategic combination therapies to realize the potential of this promising class of targeted anti-cancer agents. The review also highlights the need for biomarker identification through next-generation sequencing, initial focus on hematologic malignancies, harnessing immune effects, and conducting combination trials to maximize the therapeutic potential of PI3K/AKT/mTOR inhibitors.The central role of phosphoinositide 3-kinase (PI3K) in tumor cell biology has led to extensive efforts to target PI3K and downstream kinases like AKT and mTOR in cancer treatment. However, clinical data show limited single-agent activity of PI3K/AKT/mTOR inhibitors at tolerable doses. An exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukemia, driven by both cell-intrinsic and extrinsic activities. This review discusses key challenges and opportunities for the clinical development of PI3K/AKT/mTOR inhibitors. It emphasizes the importance of patient selection, understanding immune modulation, and strategic combination therapies to realize the potential of this promising class of targeted anti-cancer agents. The review also highlights the need for biomarker identification through next-generation sequencing, initial focus on hematologic malignancies, harnessing immune effects, and conducting combination trials to maximize the therapeutic potential of PI3K/AKT/mTOR inhibitors.