The transcriptional regulation of p16INK4a is essential for cellular aging and oncogenic stress response. This regulation involves p16INK4a transcriptional activators such as proteins Ets1 and 2 or E47. The binding of these proteins to INK4a promoter can be inhibited by proteins Id-1 or -4 after heterodimer formation. The transcriptional inhibition of p16INK4a includes also the transcriptional repression by Bmi-1, and an epigenetic regulation which appears complex and remains incompletely understood. Actually, INK4a promoter and exon1 present a CpG island which can be methylated on cytosines by DNA methyltransferases. This DNA methylation is preceded by the lysine 9 histone H3 methylation and by the deacetylation of histone H4 both involved in gene silencing. Indeed, RNA Helicase A might protect INK4a against methylation of CpG island. Furthermore, chromatin remodelling involving SWI/SNF complex, antagonist to Bmi-1, might activate INK4a expression. The analysis of INK4a regulation mechanisms and the comprehension of the epigenetic modulation of its expression may allow us to develop a rational use of new anti-neoplastic agents.