GABA_B (γ-aminobutyric acid type B) receptors are important for keeping neuronal excitability under control. Cloned GABA_B receptors do not show the expected pharmacological diversity of native receptors and it is unknown whether they contribute to pre- as well as postsynaptic functions. Here, we demonstrate that Balb/c mice lacking the GABA_B(1) subunit are viable, exhibit spontaneous seizures, hyperalgesia, hyperlocomotor activity, and memory impairment. Upon GABA_B agonist application, null mutant mice show neither the typical muscle relaxation, hypothermia, or delta EEG waves. These behavioral findings are paralleled by a loss of all biochemical and electrophysiological GABA_B responses in null mutant mice. This demonstrates that GABA_B(1) is an essential component of pre- and postsynaptic GABA_B receptors and casts doubt on the existence of proposed receptor subtypes.