In the CNS, NO is an important physiological messenger involved in the modulation of brain development, synaptic plasticity, neuroendocrine secretion, sensory processing, and cerebral blood flow [Annu. Rev. Physiol. 57 (1995) 683]. These NO actions are largely mediated by cyclic GMP (cGMP) formed by stimulation of soluble guanylyl cyclase (sGC). NO has also been recognized as a neuropathological agent in conditions such as epilepsy, stroke and neurodegenerative disorders. In these conditions, NO may contribute to excitotoxic cell death and neuroinflammatory cell damage [Brain Res. Bull. 41 (1996) 131; Glia 29 (2000) 1]. NO can be formed in every type of CNS parenchymal cell, however, cGMP appears to be formed mainly in neurons and astroglia [Annu. Rev. Physiol. 57 (1995) 683]. There is a large body of information about the regulation of NO formation in brain cells under both normal and pathological conditions but much less is known about the control of cGMP generation, in particular during neuroinflammation when there is a high NO output. Here we briefly review our present knowledge on the regulation of NO-dependent cGMP formation in brain cells under inflammatory conditions.