Commonly, circulating tumor cells (CTCs) are described as source of metastasis in cancer patients. However, in this process cancer cells of the primary tumor site need to survive the physical and biological challenges in the blood stream before leaving the circulation to become the seed of a new metastatic site in distant parenchyma. Most of the CTCs released in the blood stream will not resist those challenges and will consequently fail to induce metastasis. A few of them, however, interact closely with other blood cells, such as neutrophils, platelets, and/or macrophages to survive in the blood stream. Recent studies demonstrated that the interaction and modulation of the blood microenvironment by CTCs is pivotal for the development of new metastasis, making it an interesting target for potential novel treatment strategies. This review will discuss the recent research on the processes in the blood microenvironment with CTCs and will outline currently investigated treatment strategies.