The Myc proteins play a central role in cellular proliferation, differentiation, apoptosis and tumorigenesis. Although it is clear that multiple molecular mechanisms mediate these functions, it is unclear how individual mechanisms contribute and if different mechanisms work in concert or separately in mediating the diverse biological functions of c-Myc. Similarly, the role of post-translational modifications in regulating c-Myc molecular and biological properties has remained uncertain, despite over 20 years of research. In particular, phosphorylation of the N-terminal transcriptional regulatory domain has been shown to have a variety of consequences ranging from dramatic effects on apoptosis, tumorigenesis and c-Myc proteolysis to negligible effects on cellular transformation and transcriptional activity. This review attempts to provide a comprehensive and critical evaluation of the accumulated evidence to address the complex and controversial issues surrounding the role of post-translational modifications in c-Myc function, focusing on phosphorylation and ubiquitination of the N-terminal transcriptional regulatory domain. An overall model emerges that suggests phosphorylation and ubiquitination play critical roles in cell cycle progression, cell growth, apoptosis and tumorigenesis that are mediated by phosphorylation-dependent transcriptional activation of distinct sets of target genes and synchronized proteolysis.