Circulating tumor cells (CTCs) are a rare tumor cell subpopulation induced and selected by the tumor microenvironment’s extreme conditions. Under hypoxia and starvation, these aggressive and invasive cells are able to invade the lymphatic and circulatory systems. Escaping from the primary tumor, CTCs enter into the bloodstream to form metastatic deposits or re-establish themselves in cancer’s primary site. Although radiotherapy is widely used to cure solid malignancies, it can promote metastasis. Radiation can disrupt the primary tumor vasculature, increasing the dissemination of CTCs. Radiation also induces epithelial–mesenchymal transition (EMT) and eliminates suppressive signaling, causing the proliferation of existent, but previously dormant, disseminated tumor cells (DTCs). In this review, we collect the results and evidence underlying the molecular mechanisms of CTCs and DTCs and the effects of radiation and hypoxia in developing these cells.