Multiple factors act in concert to define the fate of disseminated tumor cells (DTC) to enter dormancy or develop overt metastases. Here, we review these factors in the context of three stages of the metastatic cascade that impact DTCs. First, cells can be programmed within the primary tumor microenvironment to promote or inhibit dissemination, and the primary tumor can condition a premetastatic niche. Then, cancer cells from the primary tumor spread through hematogenous and lymphatic routes, and the primary tumor sends cues systematically to regulate the fate of DTCs. Finally, DTCs home to their metastatic site, where they are influenced by various organ-specific aspects of the new microenvironment. We discuss these factors in the context of breast cancer, where about one-third of patients develop metastatic relapse. Finally, we discuss how the standard-of-care options for breast cancer might affect the fate of DTCs.