Exposure to hypoxia before hypoxia-ischemia (HI) confers substantial protection referred to as preconditioning (PC). We hypothesized that PC induces critical changes of genes related to apoptotic cell death to render the brain more resistant. PC hypoxia (8% O2, 36 degrees C, 3 h) was induced in rats on postnatal day (PND) 6, and the rats were killed at 0, 2, 8, and 24 h. Total RNA was extracted from cerebral cortex and analyzed using Affymetrix rat genome 230 2.0 array. PC induced significant changes in 906 genes at 0 h, 927 at 2 h, 389 at 8 h, and 114 at 24 h. Ontology analysis revealed significant alterations in genes involved in cell communication, signal transduction, transcription, phosphorylation, and transport. Genes involved in cell death/apoptosis as well as those related to brain development (cell differentiation, neurogenesis, organogenesis, blood vessel development) were overrepresented. A detailed analysis demonstrated that 77 significantly regulated genes were involved in apoptosis, specifically related to the Bcl-2 family, JNK pathway, trophic factor pathways, inositol triphosphate (PI3) kinase/Akt pathway, extrinsic or intrinsic pathway, or the p53 pathway. The study supports that the epidermal growth factor receptor family, mitogen-activated protein kinase phosphatases, and Bcl-2-related proteins and the PI3 kinase/Akt pathway may have roles in providing resistance in the developing central nervous system (CNS).