Immune evasion is a hallmark of cancer. While, there are multiple different mechanisms that cancer cells employ, myeloid deriver suppressor cells (MDSCs) are one of the key drivers of tumor mediated immune evasion. MDSCs begin as myeloid cells recruited to the tumor microenvironment where they are transformed into potent immunosuppressive cells. Our understanding of the clinical relevance of MDSCs in cancer patients, however has significantly lagged behind the preclinical literature in part due to the absence of a cognate molecule present in mice, as well as the considerable heterogeneity of MDSCs. However, if one evaluates the clinical literature through the filter of clinically robust endpoints, such as overall survival, three important phenotypes have emerged: promyelocytic, monocytic, and granulocytic. Based on these studies, MDSCs have clear prognostic importance in multiple solid tumors, and emerging data supports the utility of circulating MDSCs as a predictive marker for cancer immunotherapy, and even as an early leading marker for predicting clinical response to systemic chemotherapy in patients with advanced solid tumors. More recent preclinical data in immunosuppressed murine models suggest that MDSCs play an important role in tumor progression and the metastatic process that is independent of their immunosuppressive properties. Consequently, targeting MDSCs either in combination with cancer immunotherapy or independently as part of an approach to inhibit the metastatic process, appears to be a very clinically promising strategy. We review different approaches to target MDSCs that could potentially be tested in future clinical trials in cancer patients.