Glypican-1 (GPC-1) is a cell surface heparan sulphate proteoglycan that is critical during normal development, but which is not required for normal homoeostasis in the adult. It is, however, overexpressed in a variety of solid tumours and is known to regulate tumour growth, invasion, metastasis and progression, through modulation of tumour cell biology as well as influence on the tumour microenvironment (TME). The role of GPC-1 in the TME and on the tumour cell is broad, as GPC-1 regulates signalling by several growth factors, including FGF, HGF, TGF-β, Wnt and Hedgehog (Hh). Signalling via these pathways promotes tumour growth and invasive and metastatic ability (drives epithelial-to-mesenchymal transition (EMT)) and influences angiogenesis, affecting both tumour and stromal cells. Broad modulation of the TME via inhibition of GPC-1 may represent a novel therapeutic strategy for inhibition of tumour progression. Here, we discuss the complex role of GPC-1 in tumour cells and the TME, with discussion of potential therapeutic targeting strategies.