Deregulated c-MYC (hereafter MYC) is widely expressed in many human tumors. Myctransgenic mouse models produce diverse tumors. MYC is a strong driver of tumorigenesis and is required for tumor maintenance. MYC is therefore an attractive target for cancer treatment. However, genetic and pharmacological approaches for the targeted inactivation of MYC for the treatment of MYC-overexpressing tumors have been shown to be unsatisfactory. MYC expression is regulated by different mechanisms at transcriptional, post-transcriptional, and post-translational levels. Turnover of MYC protein is an important step that influences the expression and function of MYC. MYC turnover is predominantly controlled by the GSK3/FBW7 axis that is regulated by multiple elements. Small molecule inhibitors (SMIs) can influence the stability and activity of MYC protein by targeting the axis and its regulator elements. Wang et al. (2004) first introduced the concept of MYC-mediated synthetic lethality (MYC-SL) induced by TRAIL and DR5-agonists. Researchers have turned to synthetic lethality as a treatment strategy for MYC-overexpressing tumors. MYC function is closely associated with MYC levels. Two strategies have been developed to treat MYC-overexpressing tumors by upregulating or downregulating MYC. An SMI can induce MYC-SL by increasing MYC expression through the inactivation of the GSK3β/FBW7 axis and CK1. Elevated MYC levels lead to DNA damage, senescence, and apoptosis. An SMI can also induce MYC-SL by decreasing MYC expression through the activation of the GSK3β/FBW7 axis, the inactivation of PP2A inhibitors, and the inhibition of ARK5, AUK-A, Brd4, CDK1, CDK2, CHK1, and SAE1/2. Reduced MYC levels cause tumor regression. Some SMIs have entered phase I and II clinical trials. SMIs may be used in the near future to treat cancers co-overexpressing MYC and the corresponding MYC-SL genes.