Circulating tumor cells (CTCs) are pivotal in cancer metastasis and serve as valuable biomarkers for diagnosis, prognosis, and treatment monitoring. Traditional CTC capture methods predominantly utilize the epithelial cell adhesion molecule (EpCAM) as a marker for isolation. However, the heterogeneity of these circulating cells and the epithelial-to-mesenchymal transition process (wherein epithelial cells acquire mesenchymal characteristics) limit the efficacy of EpCAM-based capture techniques. In this paper, we critically review the role of the EpCAM in CTC capture, explore the impact of epithelial-to-mesenchymal transition on EpCAM expression, and discuss alternative biomarkers and strategies to enhance CTC isolation. By evaluating the limitations of EpCAM-mediated capture and the challenges posed by epithelial-to-mesenchymal transition, we aim to provide insights into the development of more comprehensive liquid biopsy approaches for cancer management.