The MYC oncoprotein is an essential transcription factor that regulates the expression of many genes involved in cell growth, proliferation, and metabolic pathways. Thus, it is important to keep MYC activity in check in normal cells in order to avoid unwanted oncogenic changes. Normal cells have adapted several ways to control MYC levels, and these mechanisms can be disrupted in cancer cells. One of the major ways in which MYC levels are controlled in cells is through targeted degradation by the ubiquitin-proteasome system (UPS). Here, we discuss the role of the UPS in the regulation of MYC protein levels and review some of the many proteins that have been shown to regulate MYC protein stability. In addition, we discuss how this relates to MYC transcriptional activity, human cancers, and therapeutic targeting.