Epigenetic mechanisms influence early developmental events, shaping gene expression in exciting ways that go beyond the DNA blueprint. The state of chromatin is governed by an interplay between various histone modifications, variants, nucleosome remodeling complexes, and other chromatin modifiers that work in sync to prime the chromatin for specific biological outcomes. In this chapter, we explore neural crest cells (NCCs), a critical progenitor population that retains the extensive developmental potential of their blastula origins. The formation and differentiation of NCCs into diverse cell types are influenced by the regulation of their acetylation state through various epigenetic factors. This chapter delves into the intricate interplay between histone acetylases (HATs) and deacetylases (HDACs), highlighting how these enzymes modify chromatin to create a permissive environment for the induction of NCCs and steer their fate toward the melanocytic lineage. The shift in acetylation profiles during the transition from melanocytes to melanoma suggests that the transcriptional machinery may override normal regulatory mechanisms, promoting a neural crest-like state in melanoma development. Epigenetic regulation, particularly through histone acetylation, plays a pivotal role in neural crest cell development and melanoma initiation offering potential therapeutic targets.