Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are preferentially expanded in cancer. They arise from myeloid progenitor cells that do not differentiate into mature dendritic cells (DCs), granulocytes, or macrophages, and are rather thought to play a pivotal role in immune escape and cancer progression. MDSCs are characterized by the ability to suppress T cell proliferation and cytotoxicity, inhibit natural killer T (NKT) cell activation, and induce the differentiation and expansion of regulatory T cells (Treg). MDSC levels have been shown to correlate negatively with prognosis and overall survival of patients with cancers of various types and stages. The role of MDSCs in cancer progression represents a promising target for effective cancer immunotherapy. In this review, we discuss the mechanisms of MDSC functions, their influence on tumor progression and metastasis, and finally focus on up to date nanoparticle approaches that target and antagonize MDSCs in tumor-bearing hosts. The development of multifunctional nanoparticle systems for effective imaging, assessment and manipulation of MDSCs will represent strategic theranostic innovations that may improve cancer staging, therapeutic outcomes, and overall patient survival.