MUC1 is a transmembrane mucin that is often overexpressed in metastatic cancers and often used as a diagnostic marker for metastatic progression. The extracellular domain of MUC1 can serve as a ligand for stromal and endothelial cell adhesion receptors, and the cytoplasmic domain engages in several interactions that can result in increased migration and invasion, as well as survival. In this review, we address the role of MUC1 in metastatic progression by assessing clinical studies reporting MUC1 levels at various disease stages, reviewing mouse models utilized to study the role of MUC1 in metastatic progression, discuss mechanisms of MUC1 upregulation, and detail MUC1 protein interactions and signaling events. We review interactions between MUC1 and the extracellular environment, with proteins colocalized in the plasma membrane and/or cytoplasmic proteins, and summarize the role of MUC1 in the nucleus as a transcriptional cofactor. Finally, we review recent publications describing current therapies targeting MUC1 in patients with advanced disease and the stage of these therapies in preclinical development or clinical trials.