This chapter discusses the interactions of the trophic factors and their receptors in the central nervous system CNS. A few studies have examined the role of a variety of residues in neurotrophin action by the expression of mutant or chimeric proteins. Nerve growth factor (NGF) has been shown to bind to both low and high affinity sites in neuronal cells or tissues, with only the latter correlating with biological activity. Both b-fibroblast growth factor (bFGF) and aFGF can stimulate the synthesis of NGF by astrocytes, providing a second indirect mechanism for the action of the FGFs as trophic factors. This also suggests a role for the FGFs in response to neuronal injury. A number of studies have shown that the treatment of both rodents and primates with NGF prevents degeneration of basal forebrain cholinergic neurons after fimbria-fornix transection. The FGF family has a complex set of receptors and binding molecules. Recent studies have implicated the role of heparan sulfate proteoglycans (HSPGs) in a variety of biological processes, especially the functional binding of the FGFs to their receptors. This initial step is linked to a variety of secondary signaling pathways, including phosphorylation of phospholipase C-γ, phosphoinositide release and the activation of protein kinase C, and the activation of adenylate cyclase. In vivo studies have shown that bFGF and, to a lesser extent, aFGF bind to specific, overlapping but distinct sites in the brain and that this binding is to high affinity receptors. There has been a great deal of progress in the molecular biology of the neurotrophic factors and their receptors during the past year. A number of new factors and new complex receptor families have been discovered.