Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane protein enriched on the cell surface of cancer cells, including melanoma, glioblastoma, and triple-negative breast cancer. There is growing evidence identifying GPNMB as a tumor-promoter; however, despite its biological and clinical significance, the molecular mechanisms engaged by GPNMB to promote tumorigenesis are not well understood. GPNMB promotes aggressive behaviors such as tumor cell proliferation, migration, and invasion. The extracellular domain of GPNMB shed from the cell surface interacts with integrins to facilitate in the recruitment of immune-suppressive and pro-angiogenic cells to the tumor microenvironment, thereby enhancing tumor migration and invasion. GPNMB also modulates receptor tyrosine kinases and integrin signaling in a cell autonomous fashion, leading to downstream kinase signaling that in turn triggers the expression and secretion of tumorigenic factors such as matrix metalloproteinases (MMPs) and cytokines. Therefore, GPNMB exerts its pro-tumorigenic role both intracellularly and in a paracrine fashion through shedding its extracellular domain. This review highlights the importance of GPNMB in cancer progression and discusses molecular mediators of GPNMB-induced tumor growth and invasion.