Differentiation is a complex process by which a terminal cell phenotype is determined. During neural development, in vivo cells of the nervous system reach this terminal phenotype through both preprogrammed genetic signaling and epigenetic signaling. This genetic program can set up initial organizational planes and an initial temporal sequence of events, but epigenetic signals drive much of the later gene expression and subsequent protein expression that determines different phases of differentiation. This epigenetic signaling can stimulate pluripotent cells to become more restricted in their fate, usually leading to multipotent cells and eventually to a final terminal phenotype. Epigenetic signals include a number of morphogenic and neurotrophic molecules that determine phenotype based on (1) the level of exposure to these endogenous substances, (2) the order of exposure, and (3) the mixture of exposure to these different epigenetic signaling molecules. These complex signaling events are being elucidated with advances in stem cell research in which the signals that stimulate multipotent cells to become neurons, glia, muscle, or bone are starting to be revealed (1). Because of this complexity, it is difficult to tease these different signaling events apart in many in vivo systems and this is why a reductionist approach with in vitro systems is often favored.