Neural crest cells are affected by a number of environmental factors including other cells, extracellular matrices, growth factors, and hormones. Neural crest mesenchyme differentiates when it is influenced by nearby epithelial cells. The timing of these interactions is also critical for differentiation. Interactions are often preceded by neural crest being trapped in locations rich in type II collagen. The interaction between epithelia and neural crest may be as a result of a diffusible ion or molecule - termed as "long-range diffusion mediated epithelial mesenchymal interactions". The epithelium could alternatively deposit a product into the extracellular matrix on which the neural crest migrate. Another method of interaction could be direct contact of neural crest and epithelium. This however, is the least likely method of interaction, since basal lamina and extracellular matrices prevent such an interaction.

Different environmental stimuli have been shown to affect the neural crest in various ways. Glial growth factor - a growth factor that suppresses the tendency of cells to become neurons - causes neural crest to differentiate into Schwann cells. BMP-2 and BMP-4 are known growth factors that cause differentiation of neural crest cells into autonomic neurons. Exposure of the same cells to growth factor beta causes a differentiation into smooth muscle. When neural crest is associated with FGF and then a subsequently exposed to nerve growth factor, the cells become sympathetic neurons. A known molecule produced by heart cells converts post-mitotic sympathetic neurons from a norepinephrine transmitter neuron into an acetylcholine secreting neuron.