AbstractMetastases claim more than 90% of cancer-related patient deaths and are usually seeded by a subset of circulating tumor cells shed off from the primary tumor. In circulation, circulating tumor cells are found both as single cells and as clusters of cells. The clusters of circulating tumor cells, although many fewer in number, possess much higher metastatic potential as compared to that of individual circulating tumor cells. In this review, we highlight recent insights into molecular mechanisms that can enable the formation of these clusters—(a) hybrid epithelial/mesenchymal phenotype of cells that couples their ability to migrate and adhere, and (b) intercellular communication that can spatially coordinate the cluster formation and provide survival signals to cancer cells. Building upon these molecular mechanisms, we also offer a possible mechanistic understanding of why clusters are endowed with a higher metastatic potential. Finally, we discuss the highly aggressive Inflammatory Breast Cancer as an example of a carcinoma that can metastasize via clusters and corroborates the proposed molecular mechanisms.