The PI3K/AKT/mTOR pathway is central to cancer biology, controlling key hallmarks such as cell cycle, survival, metabolism, and genomic instability. Despite its importance, clinical trials of PI3K/AKT/mTOR inhibitors have shown limited single-agent activity, though some success has been seen in chronic lymphocytic leukemia with PI3Kδ inhibitors. Challenges include the pathway's role in normal cells, feedback loops that can lead to resistance, and the need for rational combinations and patient selection. The pathway is frequently mutated in cancer, with PIK3CA and PTEN being key genes. However, targeting the pathway is complex due to redundancy and compensatory mechanisms. Several PI3K inhibitors are in clinical trials, including pan-class I inhibitors, isoform-selective inhibitors, and rapalogs. While pan-PI3K inhibitors are broad and may cause significant toxicity, isoform-selective inhibitors like GS-1101 (p110δ inhibitor) show promise, particularly in B-cell malignancies. These inhibitors can modulate the tumor immune environment, highlighting the importance of understanding immune effects. Combination therapies with other agents, such as TKIs or mTOR inhibitors, may enhance efficacy and overcome resistance. Rapalogs, though less effective as single agents, have shown benefit in certain cancers and are used in combination therapies. Active-site mTOR inhibitors are more potent than rapalogs but may have higher toxicity. Combining PI3K/AKT/mTOR inhibitors with other pathways, such as RAS/RAF/MEK/ERK, or with immune-modulating agents like BET inhibitors, may improve outcomes. Additionally, targeting components of the PI3K/mTOR network, such as eIF4E, S6K, or MNK, could provide alternative strategies. Future directions include identifying biomarkers through next-generation sequencing to guide patient selection and combination therapies. Emphasis on hematologic malignancies, where PI3K/mTOR inhibitors show promise, and harnessing immune effects through pathway modulation are key areas. Overall, a rational approach combining targeted therapies, patient selection, and immune modulation is essential to maximize the potential of PI3K/AKT/mTOR inhibitors in oncology.The PI3K/AKT/mTOR pathway is central to cancer biology, controlling key hallmarks such as cell cycle, survival, metabolism, and genomic instability. Despite its importance, clinical trials of PI3K/AKT/mTOR inhibitors have shown limited single-agent activity, though some success has been seen in chronic lymphocytic leukemia with PI3Kδ inhibitors. Challenges include the pathway's role in normal cells, feedback loops that can lead to resistance, and the need for rational combinations and patient selection. The pathway is frequently mutated in cancer, with PIK3CA and PTEN being key genes. However, targeting the pathway is complex due to redundancy and compensatory mechanisms. Several PI3K inhibitors are in clinical trials, including pan-class I inhibitors, isoform-selective inhibitors, and rapalogs. While pan-PI3K inhibitors are broad and may cause significant toxicity, isoform-selective inhibitors like GS-1101 (p110δ inhibitor) show promise, particularly in B-cell malignancies. These inhibitors can modulate the tumor immune environment, highlighting the importance of understanding immune effects. Combination therapies with other agents, such as TKIs or mTOR inhibitors, may enhance efficacy and overcome resistance. Rapalogs, though less effective as single agents, have shown benefit in certain cancers and are used in combination therapies. Active-site mTOR inhibitors are more potent than rapalogs but may have higher toxicity. Combining PI3K/AKT/mTOR inhibitors with other pathways, such as RAS/RAF/MEK/ERK, or with immune-modulating agents like BET inhibitors, may improve outcomes. Additionally, targeting components of the PI3K/mTOR network, such as eIF4E, S6K, or MNK, could provide alternative strategies. Future directions include identifying biomarkers through next-generation sequencing to guide patient selection and combination therapies. Emphasis on hematologic malignancies, where PI3K/mTOR inhibitors show promise, and harnessing immune effects through pathway modulation are key areas. Overall, a rational approach combining targeted therapies, patient selection, and immune modulation is essential to maximize the potential of PI3K/AKT/mTOR inhibitors in oncology.