Platelet-derived growth factor-D (PDGF-D) is a newly recognized growth factor that can regulate many cellular processes, including cell proliferation, transformation, invasion, and angiogenesis by specifically binding to and activating its cognate receptor PDGFR-beta. The functions of PDGF-D in human cancer progression are largely unknown. We discuss here the role of PDGF-D signaling pathway in cancer and how its deregulation is involved in tumor development and progression to metastatic disease.