Neural stem cells are defined as clonogenic cells with self-renewal capacity and the ability to generate all neural lineages. Cells with these characteristics have been isolated from the embryonic and adult Central Nervous System. Numerous reports show that extrinsic factors and intracellular mechanisms may trigger both endogenous and in vitro cultured neural stem cells to differentiate into desired cell outcomes. This plasticity opens new approaches for the use of neural stem cells as a source of cells for replacement therapy in damaged brain. In this review we present the evidence for the involvement of trophic factors, neurotransmitters, second messengers, aminoacids, and factors released by endothelial and glial cells, which have been reported to influence neural stem cells phenotypic choice in vitro and in vivo.