The evolution of melanoma, the most aggressive type of skin cancer, is triggered by

driver mutations that are acquired in the coding regions of particularly BRAF (rat fibrosarcoma

serine/threonine kinase, isoform B) or NRAS (neuroblastoma-type ras sarcoma virus) in melanocytes.

Although driver mutations strongly determine tumor progression, additional factors are likely

required and prerequisite for melanoma formation. Melanocytes are formed during vertebrate

development in a well-controlled di erentiation process of multipotent neural crest stem cells

(NCSCs). However, mechanisms determining the properties of melanocytes and melanoma cells

are still not well understood. The nerve growth factor receptor CD271 is likewise expressed in

melanocytes, melanoma cells and NCSCs and programs the maintenance of a stem-like and migratory

phenotype via a comprehensive network of associated genes. Moreover, CD271 regulates phenotype

switching, a process that enables the rapid and reversible conversion of proliferative into invasive or

non-stem-like states into stem-like states by yet largely unknown mechanisms. Here, we summarize

current findings about CD271-associated mechanisms in melanoma cells and illustrate the role of

CD271 for melanoma cell migration and metastasis, phenotype-switching, resistance to therapeutic

interventions, and the maintenance of an NCSC-like state.