Several genes have been implicated in early-onset epileptic encephalopathies, but in most cases the underlying causes remain unknown. Two independent studies have now applied exome sequencing to identify new causative mutations for these rare disorders. Lina Basel-Vanagaite, Guntram Borck and colleagues (Am. J. Hum. Genet. 93, 524–529, 2013) analyzed two unrelated individuals with early-onset epileptic encephalopathy and overlapping clinical features and identified biallelic truncating mutations in SZT2 in both subjects. Notably, mice with mutations in Szt2 are susceptible to induced seizures (Genes Brain Behav. 8, 568–576, 2009), mirroring the human phenotype. Separately, Hirotomo Saitsu and colleagues (Am. J. Hum. Genet. 93, 496–505, 2013) identified de novo mutations in GNAO1 in four individuals with epileptic encephalopathy characterized by severe intellectual disability and delays in motor development. GNAO1 encodes a heterotrimeric G protein α subunit that is known to transduce signals from adrenergic receptors and modulate the activity of calcium channels. Two of the four individuals with GNAO1 mutations also exhibited involuntary movements, and three were diagnosed with Ohtahara syndrome, highlighting the importance of G protein signaling for proper neural development.