Recent molecular and clinical studies have shown that invasion may occur very early in tumor development, thus emphasizing the potential importance of specific and sensitive detection of circulating tumor cells (CTC) and circulating tumor microemboli (CTM). The technical challenge in this field consists of finding “rare” tumor cells (just a few CTCs mixed with the approximately 10 million leukocytes and 5 billion erythrocytes in 1ml of blood) and being able to distinguish them from epithelial non-tumor cells and leukocytes. Many recent studies have discussed the clinical impact of detecting CTC/CTM. Although conflicting results have been obtained, these studies suggest the vast potential of CTC/CTM detection in cancer prognosis and follow up. However, the variable technical approaches which were used, as well as the number of millilitres of blood analyzed, the quality of sensitivity and specificity tests, the number of patients versus controls and the data interpretation make it very difficult to draw firm conclusions. A particularly important recent finding is that invasive tumor cells tend to loose their epithelial antigens by the epithelial to mesenchymal transition (EMT) process. Furthermore, it is known that non-tumor epithelial cells can also be present in blood. Thus, it appears that a reliable diagnostic identification of CTC and CTM cannot be based on the expression of epithelial-specific transcripts or antigens. Cytopathological examination of CTC/CTM, sensitively enriched from blood, represents a potentially useful alternative and can now be employed in routine analyses as a specific diagnostic assay, and be tested in large, blind, multicenter clinical trials. This basic approach can be complemented by immunological and molecular studies for further characterization of CTC/CTM and of their malignant potential. This review is aimed at helping oncologists critically evaluate past and future research work in this field. The interest in development and assessment of this noninvasive marker should lead to more effective and better tailored anticancer treatments for individual patients, thus resulting in their improved life expectancy.