Perlecan, an extracellular matrix proteoglycan, regulates signaling by a variety of growth factors through protein-protein and protein-carbohydrate interactions. Recent evidence demonstrates that Perlecan modulates sonic hedgehog signaling during both development and neoplasia, in particular in prostate cancer. Perlecan directly binds to sonic hedgehog and is required for its signaling. Increased sonic hedgehog signaling due to Perlecan in aggressive and metastatic prostate cancer cells can be attributed to increased Perlecan expression or changes in Perlecan glycan structure. Additional co-localization studies suggest that other tumor types may also have a Perlecan-modulated hedgehog signaling pathway. Inhibitors of Perlecan function at either the protein or glycan level would be ideal drug candidates for anti-cancer therapies.