Carcinoma cells found in the blood of cancer patients are predictors of metastatic progression and may guide treatment decisions. Most of the current strategies for detecting circulating tumor cells (CTC) are based on the epithelial markers epithelial cell adhesion molecule and keratin; however, evidence is accumulating that in certain tumor types, these epithelial markers are downregulated during tumor cell dissemination, hampering the detection of CTCs. This short review discusses the implications of the cellular changes of tumor cells during the metastatic cascade on CTC diagnostics.