The dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway is a key factor in cancer development and resistance to cancer treatments. Targeting PI3K and its downstream substrates, such as AKT and mTOR, has shown promise in preclinical studies and phase III trials, leading to the approval of several PI3K pathway inhibitors by the FDA. However, the clinical efficacy of these inhibitors is limited by toxicities and acquired resistance. This review discusses the PI3K signaling pathway, its alterations in various cancers, current and novel PI3K pathway inhibitors, adverse effects, resistance mechanisms, and future directions. The PI3K/AKT/mTOR pathway is crucial for cellular processes such as transcription, translation, proliferation, and survival. Dysregulation of this pathway can lead to cancer development and resistance to treatments. PI3K inhibitors, including pan-PI3K inhibitors, isoform-selective PI3K inhibitors, and PI3K/mTOR inhibitors, have been investigated in various cancers, including hematological malignancies, breast cancer, and solid tumors. While some PI3K inhibitors have shown promising results in clinical trials, others have been withdrawn due to safety concerns. The combination of PI3K inhibitors with other drugs, such as mTOR inhibitors, may overcome resistance mechanisms. The review also highlights the importance of detecting PI3K pathway alterations to guide therapeutic decisions and improve patient outcomes.The dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway is a key factor in cancer development and resistance to cancer treatments. Targeting PI3K and its downstream substrates, such as AKT and mTOR, has shown promise in preclinical studies and phase III trials, leading to the approval of several PI3K pathway inhibitors by the FDA. However, the clinical efficacy of these inhibitors is limited by toxicities and acquired resistance. This review discusses the PI3K signaling pathway, its alterations in various cancers, current and novel PI3K pathway inhibitors, adverse effects, resistance mechanisms, and future directions. The PI3K/AKT/mTOR pathway is crucial for cellular processes such as transcription, translation, proliferation, and survival. Dysregulation of this pathway can lead to cancer development and resistance to treatments. PI3K inhibitors, including pan-PI3K inhibitors, isoform-selective PI3K inhibitors, and PI3K/mTOR inhibitors, have been investigated in various cancers, including hematological malignancies, breast cancer, and solid tumors. While some PI3K inhibitors have shown promising results in clinical trials, others have been withdrawn due to safety concerns. The combination of PI3K inhibitors with other drugs, such as mTOR inhibitors, may overcome resistance mechanisms. The review also highlights the importance of detecting PI3K pathway alterations to guide therapeutic decisions and improve patient outcomes.