Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that accumulate during pathologic conditions, such as cancer. Patients diagnosed with advanced metastatic cancers have an average survival of 12-24 mo, a survival time that hasn't changed significantly in the past 30 yr. Despite some encouraging improvements in response rates and overall survival in patients receiving immunotherapies, such as immune checkpoint inhibitors, most patients will ultimately progress. MDSCs contribute to immunotherapeutic resistance by actively inhibiting antitumor T cell proliferation and cytotoxic activity as well as by promoting expansion of protumorigenic T regulatory cells, thereby, dampening the host immune responses against the tumor. In addition, MDSCs promote angiogenesis, tumor invasion, and metastasis. Thus, MDSCs are potential therapeutic targets in cases of multiple cancers. This review focuses on the phenotypic and functional characteristics of MDSCs and provides an overview of the mono- and combinatorial-therapeutic strategies that target MDSCs with an objective of enhancing the efficacy of cancer immunotherapies.