Early dissemination, blood circulation, or homing of single tumor cells in bone marrow and other organs is usually undetectable at primary diagnosis, even by high resolution imaging technologies. However, ultrasensitive approaches now enable the detection of “occult” tumor cells. Many researchers are currently focusing on circulating tumor cells (CTC) in peripheral blood, and several publications have described associations of CTC in patients with metastatic cancer and worse prognosis. However, evidence has emerged that the currently used detection methods lack sensitivity or specificity to track all CTC, especially those that have lost characteristic epithelial features. Therefore, new developments in this field are of utmost interest and will be reviewed here. Moreover, molecular CTC analysis will provide insights into the selection of tumor cells and resistance mechanisms in patients undergoing systemic therapies. This information might support assessing individual prognosis, stratifying patients at risk to systemic therapies, and monitoring therapeutic efficacy.