Abstract Virtually all adult glioblastomas contain somatic mutations resulting in elevated activity of the receptor tyrosine kinase (RTK)/Ras/PI3K signaling axis, including common loss of function mutations in PTEN, activating mutations in PIK3CA encoding p110α, the catalytic subunit of PI3Kα, or mutations in PIK3R1, encoding p85α, the regulatory subunit of PI3K. Despite an important role in sporadic glioblastoma, germline PTEN mutations do not confer an increased genetic susceptibility to brain tumors. However, inherited mutation of PTEN is associated with macrocephaly and neurological abnormalities including seizures, ataxia, autism and Lhermitte-Duclos disease. Mouse models further demonstrate that PTEN plays an essential role in development, homeostasis, and tumor suppression in the mammalian brain. Recently, germline or somatic mutations in multiple components of the PI3K signaling pathway were identified in human megalencephaly syndromes without apparent association with cancer predisposition, including mutations in PIK3CA, AKT3, PIK3R2, and MTOR. Mouse models that demonstrate the varying contributions of PI3K pathway members in brain development or tumorigenesis, and show context-dependent roles for PI3K signaling will be discussed. Citation Format: Suzanne J. Baker. PTEN and PI3K signaling in brain development and disease. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA08. doi:10.1158/1538-7445.CANSUSC14-IA08