A 43 kd protein called glia-derived nexin or protease nexin-1 (GDN/PN-1) with both neurite-promoting and serine protease inhibitor activity is developmentally regulated during the differentiation of the nervous system. The synthesis of GDN/PN-1 remains high in structures such as the olfactory system where degeneration and regeneration take place throughout life. It is also up-regulated following injury both in the peripheral and the central nervous systems. Together with hirudin (a protease inhibitor from the leech), GDN/PN-1 is the most potent thrombin inhibitor known today. The surprising discovery of this potent thrombin inhibitor in the nervous system led to demonstration that mRNAs coding for prothrombin and the thrombin receptor are detected in neural tissue. Neuronal cells can cleave the inactive prothrombin into the active thrombin, which, in turn, specifically cleaves its own receptor to trigger a metabolic cascade causing sudden neurite retraction. Other macromolecules, such as vitronectin and thrombospondin, also found in the blood, can stimulate neurite outgrowth. Altogether, the data available today indicate that many molecules considered until now to be components of the hematopoietic system could perform distinct tasks and specific functions in the nervous system. Some of the experimental facts still required for demonstration of this hypothesis are discussed.