The phosphatidylinositol 3-kinase (PI3K) pathway is a critical regulator of growth, survival, and proliferation, and its dysregulation is a common feature of human cancers. PI3K and PTEN are key components of this pathway, with PI3K promoting signaling and PTEN acting as a negative regulator by dephosphorylating the lipid intermediate PIP3. Mutations in *PIK3CA* and *PTEN* are among the most frequent in human cancers, leading to uncontrolled activation of PI3K signaling. PTEN also has additional functions beyond phosphatase activity, including roles in genomic integrity, cell migration, stem cell self-renewal, and interactions with p53. The complex regulation of PI3K signaling, including feedback mechanisms involving mTOR, poses significant challenges for therapeutic targeting. Despite these complexities, the PI3K pathway remains an important therapeutic target in cancer, with ongoing research focusing on developing selective inhibitors and understanding the context-specific functions of its components.The phosphatidylinositol 3-kinase (PI3K) pathway is a critical regulator of growth, survival, and proliferation, and its dysregulation is a common feature of human cancers. PI3K and PTEN are key components of this pathway, with PI3K promoting signaling and PTEN acting as a negative regulator by dephosphorylating the lipid intermediate PIP3. Mutations in *PIK3CA* and *PTEN* are among the most frequent in human cancers, leading to uncontrolled activation of PI3K signaling. PTEN also has additional functions beyond phosphatase activity, including roles in genomic integrity, cell migration, stem cell self-renewal, and interactions with p53. The complex regulation of PI3K signaling, including feedback mechanisms involving mTOR, poses significant challenges for therapeutic targeting. Despite these complexities, the PI3K pathway remains an important therapeutic target in cancer, with ongoing research focusing on developing selective inhibitors and understanding the context-specific functions of its components.