Neurofibromatosis type I (NF1) is a common genetic disease which leads to a variety of clinical features affecting cells of neural crest origin. In the period since the NF1 gene was isolated in 1991, our understanding of the genetics of NF1 has increased remarkably. One of the most striking aspects of NF1 genetics is its complexity, both in terms of gene organization and expression. The gene is large and, when mutated, gives rise to diverse manifestations. A growing body of data suggests that mutations in the NF1 gene alone may not be responsible for all of the features of this disease. Epigenetic mechanisms, those which affect the NF1 transcript, play a role in the normal expression of the NF1 gene. Therefore, aberrations in those epigenetic processes are most likely pathogenic. Herein we summarize salient aspects of the vast body of NF1 literature and provide some insights into the myriad of regulatory mechanisms that may go awry in the genesis of this common but complex disease.