Metastasis is the overwhelming cause of mortality in patients with breast cancer and our understanding of its cellular and molecular determinants is limited. Among cellular determinants, disseminated (DTC) tumor cells undoubtedly are key players in the metastatic cascade. In the past, several models have been constructed to explain the presence of individual tumor cells in secondary organs and their influence on the subsequent course of the disease. According to most recent transcriptome and genome analyses, DTCs are viewed as rare and much earlier indicators of metastasis than generally assumed from the typical course of breast cancer. Despite the observation that the numerous genetic alterations in such cells are rarely identical or even similar, characterization of the long interval between dissemination and clinically manifested metastases, the resistance to chemotherapy and significant effect on disease progression despite the low abundance in secondary organs, support the idea that some of these cells might be progenitor cells with self-renewing properties that give rise to most of the tumor mass that is dealt with clinically. Here, we review evidence from translational research and data from observational studies on DTCs to elucidate their potential impact for both future clinical trial design and, in the long run, decision-making in our daily patient management.