The distal metastasis of tumor cells is viewed as a series of concurrent processes rather than a linear cascade of events. Accompanied with the progression of the primary tumor, a favorable microenvironment, refered as pre-metastatic niche, has been created in pre-metastatic organs and sites by primary tumors for subsequent metastases. The proposal of “pre-metastatic niche” theory brings fresh insight into our understanding of cancer metastasis. Myeloid-derived suppressor cells (MDSCs) are indispensable for the formation of pre-metastatic niche, which empower the niche to favor tumor cell colonization and promote metastasis. In this review, we aim to provide a comprehensive understanding of the regulation of pre-metastatic niche formation by MDSCs and to conceptualize the framework for understanding the related factors involved in cancer metastasis.