The phosphatidylinositol-3-kinase (PI3K) pathway is a critical signaling pathway involved in cellular growth, survival, and metabolism, and its dysregulation is associated with various cancers. PI3K inhibitors have shown promise in preclinical studies and clinical trials, but their clinical application is limited by toxicity, resistance, and limited efficacy. This review discusses the PI3K signaling pathway, its alterations in various cancers, current and novel PI3K inhibitors, their adverse effects, resistance mechanisms, and future directions. The PI3K pathway consists of three classes (I, II, III), with class I PI3Ks being the most studied. Class I PI3Ks include PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ, which are involved in various cancers. PI3K pathway activation is linked to cancer development and resistance to treatment. PI3K inhibitors (PI3KIs) have been investigated in various cancers, including hematological malignancies, breast cancer, and solid tumors. However, their clinical efficacy is limited due to resistance mechanisms and toxicities. Several PI3KIs have been approved by the FDA, including idelalisib, copanlisib, and alpelisib. These inhibitors have shown efficacy in certain cancers but are associated with significant adverse effects. Isoform-specific PI3KIs, such as alpelisib (selective PI3Kα inhibitor), have shown better safety profiles and efficacy in specific cancers. Other PI3K inhibitors, including PI3Kδ inhibitors like idelalisib and duvelisib, have been evaluated in clinical trials for hematological malignancies but have faced challenges in clinical application due to toxicity and resistance. The PI3K pathway is also involved in resistance to other therapies, such as anti-HER2 and CDK4/6 inhibitors. Combination therapies with other drugs, such as mTOR inhibitors, have been explored to overcome resistance. However, the clinical efficacy of PI3K inhibitors remains limited, and further research is needed to improve their therapeutic potential. The review highlights the importance of molecular profiling and personalized medicine in the treatment of cancers with PI3K pathway alterations.The phosphatidylinositol-3-kinase (PI3K) pathway is a critical signaling pathway involved in cellular growth, survival, and metabolism, and its dysregulation is associated with various cancers. PI3K inhibitors have shown promise in preclinical studies and clinical trials, but their clinical application is limited by toxicity, resistance, and limited efficacy. This review discusses the PI3K signaling pathway, its alterations in various cancers, current and novel PI3K inhibitors, their adverse effects, resistance mechanisms, and future directions. The PI3K pathway consists of three classes (I, II, III), with class I PI3Ks being the most studied. Class I PI3Ks include PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ, which are involved in various cancers. PI3K pathway activation is linked to cancer development and resistance to treatment. PI3K inhibitors (PI3KIs) have been investigated in various cancers, including hematological malignancies, breast cancer, and solid tumors. However, their clinical efficacy is limited due to resistance mechanisms and toxicities. Several PI3KIs have been approved by the FDA, including idelalisib, copanlisib, and alpelisib. These inhibitors have shown efficacy in certain cancers but are associated with significant adverse effects. Isoform-specific PI3KIs, such as alpelisib (selective PI3Kα inhibitor), have shown better safety profiles and efficacy in specific cancers. Other PI3K inhibitors, including PI3Kδ inhibitors like idelalisib and duvelisib, have been evaluated in clinical trials for hematological malignancies but have faced challenges in clinical application due to toxicity and resistance. The PI3K pathway is also involved in resistance to other therapies, such as anti-HER2 and CDK4/6 inhibitors. Combination therapies with other drugs, such as mTOR inhibitors, have been explored to overcome resistance. However, the clinical efficacy of PI3K inhibitors remains limited, and further research is needed to improve their therapeutic potential. The review highlights the importance of molecular profiling and personalized medicine in the treatment of cancers with PI3K pathway alterations.