The PI3K pathway is a central regulator of cellular metabolism and immune function, with significant implications for cancer and other diseases. This review highlights the roles of class I PI3Ks in these processes and discusses recent advances in developing PI3K-targeted therapies. The PI3K pathway is activated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is a hallmark of cancer. Many PI3K pathway inhibitors have been tested in clinical trials, with some showing regulatory approval for certain cancers. However, the development of PI3K inhibitors has been challenged by dose-limiting, on-target adverse effects. Understanding the roles of PI3K in cellular metabolism and immune regulation is crucial for developing more effective and safer therapies. The PI3K pathway is involved in a wide range of cellular processes, including cell growth, metabolism, migration, and secretion. Aberrations in PI3K signaling contribute to various diseases, including cancer, immunological disorders, neurological disorders, diabetes, and cardiovascular disease. Recent studies have shown that PI3K signaling is involved in the regulation of immune cell development and function, and that targeting PI3K in immune cells can reprogram the immune system to combat solid tumors. The PI3K pathway is also involved in innate and adaptive immunity, with distinct roles in different immune cell types. The review discusses the mechanisms of PI3K activation, the roles of different PI3K isoforms, and the impact of PI3K mutations on disease. It also highlights the importance of understanding the complex interactions between PI3K signaling and other pathways in the development of effective therapies. The review emphasizes the need for a deeper understanding of the PI3K pathway to develop more targeted and effective treatments for cancer and other diseases.The PI3K pathway is a central regulator of cellular metabolism and immune function, with significant implications for cancer and other diseases. This review highlights the roles of class I PI3Ks in these processes and discusses recent advances in developing PI3K-targeted therapies. The PI3K pathway is activated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is a hallmark of cancer. Many PI3K pathway inhibitors have been tested in clinical trials, with some showing regulatory approval for certain cancers. However, the development of PI3K inhibitors has been challenged by dose-limiting, on-target adverse effects. Understanding the roles of PI3K in cellular metabolism and immune regulation is crucial for developing more effective and safer therapies. The PI3K pathway is involved in a wide range of cellular processes, including cell growth, metabolism, migration, and secretion. Aberrations in PI3K signaling contribute to various diseases, including cancer, immunological disorders, neurological disorders, diabetes, and cardiovascular disease. Recent studies have shown that PI3K signaling is involved in the regulation of immune cell development and function, and that targeting PI3K in immune cells can reprogram the immune system to combat solid tumors. The PI3K pathway is also involved in innate and adaptive immunity, with distinct roles in different immune cell types. The review discusses the mechanisms of PI3K activation, the roles of different PI3K isoforms, and the impact of PI3K mutations on disease. It also highlights the importance of understanding the complex interactions between PI3K signaling and other pathways in the development of effective therapies. The review emphasizes the need for a deeper understanding of the PI3K pathway to develop more targeted and effective treatments for cancer and other diseases.