The onset of cancer is a complex process that is driven by the accumulation of multiple genetic mutations. However, the fact that inhibition of a single oncogene can impair the proliferation and survival of cancer cells due to their “oncogene addiction” provides implications for the so-called “molecular targeted therapy” in cancer treatment. The oncogenic transcription factor c-Myc is overexpressed in many types of cancers, and as a typical oncogene to which many cancers are addicted, c-Myc is necessary for the rapid proliferation of cancer cells. Strategies aimed at targeting c-Myc, including interfering with c-Myc synthesis, stability and transcriptional activity, have emerged as effective cancer treatments. We have recently shown that a natural agent, oridonin, promotes the Fbw7-mediated proteasomal degradation of c-Myc, leading to subsequent cell growth inhibition and apoptosis and demonstrating a new c-Myc-targeting strategy. Despite the effectiveness of molecular targeting in cancer treatment, failure to achieve long-lasting efficacy with a single agent is observed because cancer cells can recover from oncogene addiction as a result of their genomic instability and heterogeneity. Combined cancer therapies were therefore developed and showed better efficacies than single-agent therapy in cancer cell lines and mouse models. Combined therapy based on c-Myc targeting can be achieved through various strategies. Agents that also target c-Myc but use different mechanisms, or agents that act on other genes in the c-Myc pathway, can be selected for combination. In addition, the targeting of genes involved in different cellular processes in other pathways might also be a successful strategy. Regardless of the therapy adopted, it is important to first determine the molecular mechanisms underlying the agents to inform the therapy design. Among the various targets of therapeutic agents is a family of noncoding small RNAs, called microRNAs, that have been implicated in the anti-cancer activity of many therapeutic agents. c-Myc, as a transcription factor, regulates the expression of many microRNAs and is in turn regulated by microRNAs. Combining c-Myc-targeting agents with those that target microRNAs might provide a novel approach for cancer therapy.