The second messenger cyclic guanosine-3',5'-monophosphate (cGMP) mediates many effects of nitric oxide in the nervous system. cGMP may act through various intracellular receptors, among them a family of serine/threonine kinases, the cGMP-dependent protein kinases (cGKs). Hitherto, three mammalian cGKs have been identified: cGKIalpha, cGKIbeta and cGKII. Discrete functions of cGKI and cGKII are determined by their distinct expression patterns and targeting to specific substrates. This review provides an overview about the expression and functions of cGKs in the nervous system. Main emphasis is put on the discussion of phenotypes observed in cGK-deficient mouse models that lack cGKI and/or cGKII globally or selectively in brain regions of interest. Recent data demonstrate important functions of cGKI in (1) the development and sensitization of nociceptive neurons, and (2) synaptic plasticity and learning. There is also evidence suggesting that cGKII in the suprachiasmatic nucleus of the hypothalamus is involved in the regulation of circadian rhythmicity. Thus, cGKs serve key functions in the transduction of cGMP signals into cellular responses in distinct regions of the nervous system.-