The interplay between discrete neoplastic cells and cells within the tumor microenvironment represents a critical component of cancer evolution that ultimately impacts patient outcomes. A newly identified neoplastic cell that is a product of cell fusion between neoplastic and immune cells has emerged as a key player in metastatic spread. Indeed, these hybrid cells are detected across the metastatic cascade: within the primary tumor, disseminated into the peripheral blood, and in metastatic sites. While multiple mechanisms of hybrid cells generation have been posited, cell fusion has the most rigorous prior study. Most commonly between tumor cells and macrophages, fusion progeny are identified by the co-expression of parental cell type features (e.g., epithelial proteins and immune cell antigens). After fusion, they become reprogrammed to be distinct from other neoplastic cells and demonstrate properties that enhance their ability to successfully travel through the metastatic cascade. As such, cell fusion hybrids have more recently gained traction as a means of tumorigenesis, metastatic spread, and treatment resistance. Importantly, investigators have demonstrated clinical utility for disseminated tumor-immune hybrids, called circulating hybrid cells (CHCs) in peripheral blood, for early detection, metastatic risk stratification, treatment resistance, and disease progression. Herein, we review the study of tumor hybrid cells as a new frontier of cancer biology and as a developing biomarker to enhance metrics for cancer patient care and survival.