Activation of invasion and metastasis is a central hallmark of cancer, contributing to the primary cause of death for cancer patients. In the multistep metastatic process, cancer cells must infiltrate the circulation, survive, arrest at capillary beds, extravasate, and form metastatic clones in distant organs. However, only a small proportion of circulating tumor cells (CTCs) successfully form metastases, with transit of CTCs in the circulation being the rate-limiting step. The fate of CTCs is influenced by the circulating tumor microenvironment (cTME), which encompasses factors affecting their biological behaviors in the circulation. This liquid and flowing microenvironment differs significantly from the primary tumor microenvironment or the pre-metastatic niche. This review summarizes the latest advancements in identifying the biophysical cues, key components, and biological roles of the cTME, highlighting the network among biophysical attributes, blood cells, and non-blood factors in cancer metastasis. In addition to the potential of the cTME as a therapeutic target for inhibiting metastasis, the cTME could also represent as a biomarker for predicting patient outcomes and developing strategies for treating cancer.