The epithelial–mesenchymal transition (EMT) program is critical to metastatic cancer progression. EMT results in the expression of mesenchymal proteins and enhances migratory and invasive capabilities. In a small percentage of cells, EMT results in the expression of stemness-associated genes that provide a metastatic advantage. Although EMT had been viewed as a binary event, it has recently become clear that the program leads to a spectrum of phenotypes, including hybrid epithelial/mesenchymal (E/M) cells that have significantly greater metastatic capability than cells on the epithelial or mesenchymal ends of the spectrum. As hybrid E/M cells are rarely observed in physiological, non-diseased states in the adult human body, these cells are potential biomarkers and drug targets. Hybrid E/M cells are distinguished by the co-expression of epithelial and mesenchymal proteins, such as the intermediate filament proteins cytokeratin (CK; epithelial) and vimentin (VIM; mesenchymal). Although these intermediate filaments have been extensively used for pathological characterization and detection of aggressive carcinomas, little is known regarding the interactions between CK and VIM when co-expressed in hybrid E/M cells. This review describes the characteristics of hybrid E/M cells with a focus on the unique co-expression of VIM and CK. We will discuss the structures and functions of these two intermediate filament proteins and how they may interact when co-expressed in hybrid E/M cells. Additionally, we review what is known about cell-surface expression of these intermediate filament proteins and discuss their potential as predictive biomarkers and therapeutic targets.