Podoplanin, a small mucin-type sialoglycoprotein, was recently shown to be involved in tumor progression. Podoplanin is overexpressed in cancer cells of various human malignancies, and recently, it is also detected in intratumoral stromal cells. We now appreciate that podoplanin plays a dual role in cancer: it can not only suppress tumor growth but also promote tumor progression. Researchers have identified several potential pathways invoked by podoplanin, which participate in the epithelial-to-mesenchymal transition, collective-cell migration, platelet activation and aggregation, and lymphangiogenesis, and thus regulate the tumor invasion and metastasis. Here, we discuss the current experimental and human clinical data on podoplanin to validate the multiple context-dependent functions in different microenvironments and to delineate the diverse regulatory mechanisms.