Heparin/heparan sulfate-like glycosaminoglycans (HSGAGs) are involved in diverse cellular processes in the extracellular matrix (ECM). The biological effect of HSGAGs depends on disaccharide content and physiological location within the ECM. HSGAGs are also brought into cells during membrane transcytosis and growth factor signaling while protein bound. We sought to probe the impact of free HSGAGs within the cell by using heparin as a model HSGAG. A library of poly(beta-amino ester)s, which internalize DNA, was examined for the capacity of its members to internalize heparin. Fourteen polymers enabled heparin internalization. The most efficacious polymer reduced murine melanoma cell growth by 73%. No glycosaminoglycan was as efficacious as highly sulfated, full-length heparin. Internalized heparin likely interferes with transcription factor function and subsequently induces apoptotic cell death. Therefore, internalized heparin is a novel mechanism for inducing apoptosis of cancer cells.